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Luo Y, Liu Q, Mao Y, Wen J, Chen G. Different action of glucocorticoid receptor in adipose tissue remodelling to modulate energy homeostasis by chronic restraint stress. Lipids Health Dis 2025; 24:121. [PMID: 40148860 PMCID: PMC11948944 DOI: 10.1186/s12944-025-02539-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Chronic stress in daily life is a well-known trigger for various health issues. Despite advancements in obesity research, the mechanisms governing lipid metabolism in adipose tissue during cachexia remain poorly understood. METHODS A chronic restraint stress (CRS) model was used to induce significant physiological and psychological stress in mice. Mice were subjected to 6 h of restraint daily in 50 mL plastic tubes for seven consecutive days. A fasting control group was included for comparison. Post-stress assessments included behavioural tests, glucose and insulin tolerance tests and indirect calorimetry. Blood and adipose tissue samples were collected for mRNA and protein analyses. RESULTS CRS induced significant psychological and physiological changes in mice, including depression-like behaviours, weight loss and reduced insulin sensitivity. Notably, CRS caused extensive adipose tissue remodelling. White adipose tissue (WAT) underwent significant 'browning' accompanied by an increase in the expression of thermogenic proteins. This counteracted the stress-induced 'whitening' of brown adipose tissue (BAT), which exhibited impaired thermogenesis and functionality, thereby maintaining energy balance systematically. The glucocorticoid receptor (GR) plays a crucial role in lipid metabolism regulation during these changes. GR expression levels were inversely correlated in BAT and WAT, but aligned with the expression patterns of thermogenic proteins across adipose tissues. These findings suggest that under chronic metabolic stress, GR mediates tissue-specific responses in adipose tissues, driving functional and phenotypic transitions in BAT and WAT to maintain energy homeostasis. CONCLUSIONS This study provides novel insights into the contrasting thermogenic phenotypes of BAT and WAT under emaciation and highlights the critical role of GRs in adipose tissue remodelling during CRS and its potential as a therapeutic target. Addressing GR-mediated changes in adipose tissues may help alleviate BAT dysfunction in cachexia and promote WAT browning, enhancing metabolic stress resistance.
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Affiliation(s)
- Yinghua Luo
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Qinyu Liu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Yaqian Mao
- Department of Endocrinology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Junping Wen
- Department of Endocrinology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Gang Chen
- Department of Endocrinology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China.
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2
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Cantave CY, Ruttle PL, Coté SM, Lupien SJ, Geoffroy MC, Vitaro F, Brendgen M, Tremblay R, Boivin M, Ouellet-Morin I. Body mass index across development and adolescent hair cortisol: the role of persistence, variability, and timing of exposure. Int J Obes (Lond) 2025; 49:125-132. [PMID: 39367209 DOI: 10.1038/s41366-024-01640-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 09/09/2024] [Accepted: 09/24/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND Research suggests a putative role of the glucocorticoid stress hormone cortisol in the accumulation of adiposity. However, obesity and weight fluctuations may also wear and tear physiological systems promoting adaptation, affecting cortisol secretion. This possibility remains scarcely investigated in longitudinal research. This study tests whether trajectories of body mass index (BMI) across the first 15 years of life are associated with hair cortisol concentration (HCC) measured two years later and whether variability in BMI and timing matter. METHODS BMI (kg/m2) was prospectively measured at twelve occasions between age 5 months and 15 years. Hair was sampled at age 17 in 565 participants. Sex, family socioeconomic status, and BMI measured concurrently to HCC were considered as control variables. RESULTS Latent class analyses identified three BMI trajectories: "low-stable" (59.2%, n = 946), "moderate" (32.6%, n = 507), and "high-rising" (8.2%, n = 128). BMI variability was computed by dividing the standard deviation of an individual's BMI measurements by the mean of these measurements. Findings revealed linear effects, such that higher HCC was noted for participants with moderate BMI trajectories in comparison to low-stable youth (β = 0.10, p = 0.03, 95% confidence interval (CI) = [0.02-0.40]); however, this association was not detected in the high-rising BMI youth (β = -0.02, p = 0.71, 95% CI = [-0.47-0.32]). Higher BMI variability across development predicted higher cortisol (β = 0.17, p = 0.003, 95% CI = [0.10-4.91]), additively to the contribution of BMI trajectories. BMI variability in childhood was responsible for that finding, possibly suggesting a timing effect. CONCLUSIONS This study strengthens empirical support for BMI-HCC association and suggests that more attention should be devoted to BMI fluctuations in addition to persistent trajectories of BMI.
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Affiliation(s)
- Christina Y Cantave
- Institute of Child Development, University of Minnesota-Twin Cities, 51 E River Parkway, Minneapolis, MN, 55455, USA
| | - Paula L Ruttle
- Translational Neuroscience, Oregon State University, Corvallis, OR, USA
| | - Sylvana M Coté
- Department of Social and Preventive Medicine, University of Montreal, C.P. 6128, succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
- Sainte-Justine Hospital Research Center, 3175 Côte-Sainte-Catherine Road, Montréal, QC, H3T 1C5, Canada
| | - Sonia J Lupien
- Centre for Studies on Human Stress, Research Center of the Montreal Mental Health University Institute, 7331, rue Hochelaga, Montréal, QC, H1N 3V2, Canada
- Department of Psychiatry, University of Montreal, C.P. 6128, succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
| | - Marie-Claude Geoffroy
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, 6875 LaSalle Boulevard, Montreal, QC, H4A 1R3, Canada
| | - Frank Vitaro
- Sainte-Justine Hospital Research Center, 3175 Côte-Sainte-Catherine Road, Montréal, QC, H3T 1C5, Canada
- School of Psychoeducation, University of Montreal, C.P. 6128, succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
| | - Mara Brendgen
- Sainte-Justine Hospital Research Center, 3175 Côte-Sainte-Catherine Road, Montréal, QC, H3T 1C5, Canada
- Department of Psychology, Université du Québec à Montréal, C.P. 8888 succursale Centre-ville, Montréal, QC, H3C 3P8, Canada
| | - Richard Tremblay
- Department of Pediatrics and Psychology, University of Montreal, C.P. 6128, succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
- School of Public Health, Physiotherapy and Population Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Michel Boivin
- School of Psychology, Laval University, 2325 rue des Bibliothèques, Bureau 1116, Quebec City, QC, G1V 0A6, Canada
| | - Isabelle Ouellet-Morin
- Centre for Studies on Human Stress, Research Center of the Montreal Mental Health University Institute, 7331, rue Hochelaga, Montréal, QC, H1N 3V2, Canada.
- School of Criminology, University of Montreal, C.P. 6128, succursale Centre-ville, Montréal, QC, H3C 3J7, Canada.
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Nowell A, Torres SJ, Hall SJ, Keske MA, Torpy DJ, Parker L, Betik AC, Turner AI. Is high salt intake inducing obesity via production of cortisol? A novel working hypothesis and pilot study. Eur J Nutr 2024; 63:1315-1327. [PMID: 38409436 PMCID: PMC11139711 DOI: 10.1007/s00394-024-03354-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 02/13/2024] [Indexed: 02/28/2024]
Abstract
PURPOSE Evidence is growing that high salt intake is an independent risk factor for obesity, but the mechanisms are unknown. Our novel working hypothesis is that high salt intake drives cortisol production, which in turn, drives obesity. The current study aimed to demonstrate an acute cortisol response following a single high salt meal. METHODS Eight participants (age 30.5 ± 9.8 years [mean ± SD], 50% female), consumed high salt (3.82 g; 1529 mg sodium) and low salt (0.02 g; 9 mg sodium) meals in a randomized cross-over design. RESULTS Urinary and salivary cortisol and plasma adrenocorticotropic hormone (ACTH) demonstrated order effects. When high salt was given second, there was a peak above baseline for urinary cortisol (26.3%), salivary cortisol (9.4%) and plasma ACTH (4.1%) followed by a significant decline in each hormone (treatment*time, F[9, 18] = 2.641, p = 0.038, partial η2 = 0.569; treatment*time, F[12, 24] = 2.668, p = 0.020, partial η2 = 0.572; treatment*time, F[12, 24] = 2.580, p = 0.023, partial η2 = 0.563, respectively), but not when high salt was given first (p > 0.05 for all). CONCLUSION These intriguing findings provide partial support for our hypothesis and support a need for further research to elucidate the role of high salt intake in cortisol production and, in turn, in the aetiology of obesity. TRIAL REGISTRATION NUMBER ACTRN12623000490673; date of registration 12/05/2023; retrospectively registered.
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Affiliation(s)
- Anthony Nowell
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia
| | - Susan J Torres
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia
| | - Sarah J Hall
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia
| | - Michelle A Keske
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia
| | - David J Torpy
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Lewan Parker
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia
| | - Andrew C Betik
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia
| | - Anne I Turner
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia.
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Moran KM, Delville Y. A hamster model for stress-induced weight gain. Horm Behav 2024; 160:105488. [PMID: 38306877 DOI: 10.1016/j.yhbeh.2024.105488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 12/18/2023] [Accepted: 01/18/2024] [Indexed: 02/04/2024]
Abstract
This review addresses the translational relevance of animal models of stress and their effects on body weight. In humans, stress, whether chronic or acute, has often been associated with increased food intake and weight gain. In view of the current obesity epidemic, this phenomenon is especially relevant. Such observations contrast with reports with commonly used laboratory animals, especially rats and mice. In these species, it is common to find individuals gaining less weight under stress, even with potent social stressors. However, there are laboratory species that present increased appetite and weight gain under stress, such as golden hamsters. Furthermore, these animals also include metabolic and behavioral similarities with humans, including hoarding behavior which is also enhanced under stress. Consequently, we propose that our comparative perspective provides useful insights for future research on the development of obesity in humans as a consequence of chronic stress exposure.
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Affiliation(s)
- Kevin M Moran
- Psychology Department, The University of Texas at Austin, USA.
| | - Yvon Delville
- Psychology Department, The University of Texas at Austin, USA
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Paul B, Buchholz DR. Minireview: Glucocorticoid-Leptin Crosstalk: Role of Glucocorticoid-Leptin Counterregulation in Metabolic Homeostasis and Normal Development. Integr Comp Biol 2023; 63:1127-1139. [PMID: 37708034 DOI: 10.1093/icb/icad119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 08/16/2023] [Accepted: 08/30/2023] [Indexed: 09/16/2023] Open
Abstract
Glucocorticoids and leptin are two important hormones that regulate metabolic homeostasis by controlling appetite and energy expenditure in adult mammals. Also, glucocorticoids and leptin strongly counterregulate each other, such that chronic stress-induced glucocorticoids upregulate the production of leptin and leptin suppresses glucocorticoid production directly via action on endocrine organs and indirectly via action on food intake. Altered glucocorticoid or leptin levels during development can impair organ development and increase the risk of chronic diseases in adults, but there are limited studies depicting the significance of glucocorticoid-leptin interaction during development and its impact on developmental programming. In mammals, leptin-induced suppression of glucocorticoid production is critical during development, where leptin prevents stress-induced glucocorticoid production by inducing a period of short-hyporesponsiveness when the adrenal glands fail to respond to certain mild to moderate stressors. Conversely, reduced or absent leptin signaling increases glucocorticoid levels beyond what is appropriate for normal organogenesis. The counterregulatory interactions between leptin and glucocorticoids suggest the potential significant involvement of leptin in disorders that occur from stress during development.
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Affiliation(s)
- Bidisha Paul
- Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Daniel R Buchholz
- Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA
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Wallace T, Myers B. Prefrontal representation of affective stimuli: importance of stress, sex, and context. Cereb Cortex 2023; 33:8232-8246. [PMID: 37032618 PMCID: PMC10321111 DOI: 10.1093/cercor/bhad110] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 03/08/2023] [Accepted: 03/09/2023] [Indexed: 04/11/2023] Open
Abstract
Stress-related disorders such as depression and anxiety exhibit sex differences in prevalence and negatively impact both mental and physical health. Affective illness is also frequently accompanied by changes in ventromedial prefrontal cortical (vmPFC) function. However, the neurobiology that underlies sex-specific cortical processing of affective stimuli is poorly understood. Although rodent studies have investigated the prefrontal impact of chronic stress, postmortem studies have focused largely on males and yielded mixed results. Therefore, genetically defined population recordings in behaving animals of both sexes were used to test the hypothesis that chronic variable stress (CVS) impairs the neural processing of affective stimuli in the rodent infralimbic region. Here, we targeted expression of a calcium indicator, GCaMP6s, to infralimbic pyramidal cells. In males, CVS reduced infralimbic responses to social interaction and restraint stress but increased responses to novel objects and food reward. In contrast, females did not have CVS-induced changes in infralimbic activity, which was partially dependent on the ovarian status. These results indicate that both male and female vmPFC cells encode social, stress, and reward stimuli. However, chronic stress effects are sex-dependent and behavior-specific. Ultimately, these findings extend the understanding of chronic stress-induced prefrontal dysfunction and indicate that sex is a critical factor for cortical processing of affective stimuli.
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Affiliation(s)
- Tyler Wallace
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
| | - Brent Myers
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
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Ahmed M, Cerda I, Maloof M. Breaking the vicious cycle: The interplay between loneliness, metabolic illness, and mental health. Front Psychiatry 2023; 14:1134865. [PMID: 36970267 PMCID: PMC10030736 DOI: 10.3389/fpsyt.2023.1134865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/24/2023] [Indexed: 03/11/2023] Open
Abstract
Loneliness, or perceived social isolation, is a leading predictor of all-cause mortality and is increasingly considered a public health epidemic afflicting significant portions of the general population. Chronic loneliness is itself associated with two of the most pressing public health epidemics currently facing the globe: the rise of mental illness and metabolic health disorders. Here, we highlight the epidemiological associations between loneliness and mental and metabolic health disorders and argue that loneliness contributes to the etiology of these conditions by acting as a chronic stressor that leads to neuroendocrine dysregulation and downstream immunometabolic consequences that manifest in disease. Specifically, we describe how loneliness can lead to overactivation of the hypothalamic-pituitary-adrenal axis and ultimately cause mitochondrial dysfunction, which is implicated in mental and metabolic disease. These conditions can, in turn, lead to further social isolation and propel a vicious cycle of chronic illness. Finally, we outline interventions and policy recommendations that can reduce loneliness at both the individual and community levels. Given its role in the etiology of the most prevalent chronic diseases of our time, focusing resources on alleviating loneliness is a vitally important and cost-effective public health strategy.
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Affiliation(s)
- Minhal Ahmed
- Harvard Medical School, Boston, MA, United States
| | - Ivo Cerda
- Harvard Medical School, Boston, MA, United States
| | - Molly Maloof
- Adamo Bioscience, Inc., Fernandina Beach, FL, United States
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8
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Helman TJ, Headrick JP, Stapelberg NJC, Braidy N. The sex-dependent response to psychosocial stress and ischaemic heart disease. Front Cardiovasc Med 2023; 10:1072042. [PMID: 37153459 PMCID: PMC10160413 DOI: 10.3389/fcvm.2023.1072042] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 04/03/2023] [Indexed: 05/09/2023] Open
Abstract
Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome-a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.
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Affiliation(s)
- Tessa J. Helman
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
- Correspondence: Tessa J. Helman
| | - John P. Headrick
- Schoolof Pharmacy and Medical Sciences, Griffith University, Southport, QLD, Australia
| | | | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
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9
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Wang M, Jiao H, Zhao J, Lin H, Wang X. The involvement of FATP1 regulating skeletal muscle fat deposition in stressed broilers was affected by fatty acid substrates. Front Vet Sci 2022; 9:965894. [PMID: 35909684 PMCID: PMC9334852 DOI: 10.3389/fvets.2022.965894] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Fatty acid transport protein 1 (FATP1), plays a major role in the transport and uptake of fatty acids into cells. The effect of FATP1 on the regulation of skeletal muscle fat uptake and deposition in stressed broiler chickens was investigated both in vivo and in vitro, and the effect of different fatty acid substrates were also included. Dexamethasone (DEX), a synthetic glucocorticoid (GCs), was employed to induce a hyper glucocorticoid milieu and simulate stress. The in vivo results showed that DEX would increase the mRNA expression of FATP1 and fat deposition in muscle tissues (P < 0.05), the very-low-density lipoprotein (VLDL) and insulin (INS) levels were significantly increased in the plasma by DEX (P < 0.05), and the mRNA levels of the glucocorticoid receptor (GR), adiponectin receptor (ADPNR) and peroxisomal proliferator-activated receptor α (PPARα) in thigh were also up-regulated by DEX (P < 0.05). In vitro experiment, DEX did not affect the myoblast fat deposition and PPARα and FATP1 expressions without the external fatty acid (P > 0.05). Under PA pre-treatment, both myoblast fatty acid uptake and fat deposition were promoted by DEX treatment (P < 0.05), and the effects of DEX on the gene expressions of GR, ADPNR, PPARα and FATP1 were upregulated first and then downregulated as the dose of DEX increases; while under OA pre-treatment, the myoblast fat deposition was not affected by DEX (P > 0.05), the fatty acid uptake was decreased by DEX at 500 nM compared to control (P < 0.05). When GR and PPARα were, respectively inhibited by specific inhibitors RU486 and GW6471, the effects of DEX on fatty acid uptake were reversed for PA pre-treated myoblasts (P < 0.05) but not for OA pre-treated myoblasts (P > 0.05). These results indicate that FATP1 regulation by GCs was affected by fatty acid substrate - saturated fatty acids were favorable for fat uptake and deposition, while unsaturated fatty acids were not. GCs may affect the ADPNR-PPARα-FATP1 pathway by binding to its receptors, thus regulating the uptake of saturated fatty acids into myoblasts.
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Tholen S, Patel R, Agas A, Kovary KM, Rabiee A, Nicholls HT, Bielczyk-Maczyńska E, Yang W, Kraemer FB, Teruel MN. Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy. Cell Rep 2022; 39:111018. [PMID: 35767959 PMCID: PMC9391061 DOI: 10.1016/j.celrep.2022.111018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 04/14/2022] [Accepted: 06/08/2022] [Indexed: 11/03/2022] Open
Abstract
Disruption of circadian glucocorticoid oscillations in Cushing's disease and chronic stress results in obesity and adipocyte hypertrophy, which is believed to be a main source of the harmful effects of obesity. Here, we recapitulate stress due to jet lag or work-life imbalances by flattening glucocorticoid oscillations in mice. Within 3 days, mice achieve a metabolic state with persistently high insulin, but surprisingly low glucose and fatty acids in the bloodstream, that precedes a more than 2-fold increase in brown and white adipose tissue mass within 3 weeks. Transcriptomic and Cd36-knockout mouse analyses show that hyperinsulinemia-mediated de novo fatty acid synthesis and Cd36-mediated fatty acid uptake drive fat mass increases. Intriguingly, this mechanism by which glucocorticoid flattening causes acute hyperinsulinemia and adipocyte hypertrophy is unexpectedly beneficial in preventing high levels of circulating fatty acids and glucose for weeks, thus serving as a protective response to preserve metabolic health during chronic stress.
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Affiliation(s)
- Stefan Tholen
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Roma Patel
- Department of Biochemistry and the Gale and Ira Drukier Institute of Children's Health, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Agnieszka Agas
- Department of Biochemistry and the Gale and Ira Drukier Institute of Children's Health, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Kyle M Kovary
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Atefeh Rabiee
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Hayley T Nicholls
- Weill Center for Metabolic Health, Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Ewa Bielczyk-Maczyńska
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Wenting Yang
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Fredric B Kraemer
- Department of Medicine, Division of Endocrinology, Stanford University, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA 94305, USA
| | - Mary N Teruel
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry and the Gale and Ira Drukier Institute of Children's Health, Weill Cornell Medical College of Cornell University, New York, NY, USA; Weill Center for Metabolic Health, Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
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11
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Dlamini SN, Lombard Z, Micklesfield LK, Crowther N, Norris SA, Snyman T, Crawford AA, Walker BR, Goedecke JH. Glucocorticoids associate with cardiometabolic risk factors in black South Africans. Endocr Connect 2021; 10:873-884. [PMID: 34261039 PMCID: PMC8346194 DOI: 10.1530/ec-21-0195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/14/2021] [Indexed: 01/10/2023]
Abstract
Circulating glucocorticoids are associated with metabolic syndrome and related cardiometabolic risk factors in non-Africans. This study investigated these associations in Africans, whose metabolic phenotype reportedly differs from Europeans. Adiposity, blood pressure, glycaemia, insulin resistance, and lipid profile, were measured in 316 African men and 788 African women living in Soweto, Johannesburg. The 2009 harmonized criteria were used to define metabolic syndrome. Serum glucocorticoids were measured using liquid chromatography-mass spectrometry. Cortisol was associated with greater odds presenting with metabolic syndrome (odds ratio (95% CI) =1.50 (1.04, 2.17) and higher systolic (beta coefficient, β (95% CI) =0.04 (0.01, 0.08)) and diastolic (0.05 (0.02, 0.09)) blood pressure, but higher HDL (0.10 (0.02, 0.19)) and lower LDL (-0.14 (-0.24, -0.03)) cholesterol concentrations, in the combined sample of men and women. In contrast, corticosterone was only associated with higher insulin sensitivity (Matsuda index; 0.22 (0.03, 0.41)), but this was not independent of BMI. Sex-specific associations were observed, such that both cortisol and corticosterone were associated with higher fasting glucose (standardized β (95% CI): 0.24 (0.12, 0.36) for cortisol and 0.12 (0.01, 0.23) for corticosterone) and HbA1c (0.13 (0.01, 0.25) for cortisol and 0.12 (0.01, 0.24) for corticosterone) in men only, but lower HbA1c (0.10 (-0.20, -0.01) for cortisol and -0.09 (-0.18, -0.03) for corticosterone) in women only. Our study reports for the first time that associations between circulating glucocorticoid concentrations and key cardiometabolic risk factors exhibit both glucocorticoid- and sex-specificity in Africans.
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Affiliation(s)
- Siphiwe N Dlamini
- SAMRC/Wits Developmental Pathways for Health Research Unit (DPHRU), School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Non-communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa
| | - Zané Lombard
- Division of Human Genetics, National Health Laboratory Service, and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Lisa K Micklesfield
- SAMRC/Wits Developmental Pathways for Health Research Unit (DPHRU), School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Nigel Crowther
- Department of Chemical Pathology, National Health Laboratory Service and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Shane A Norris
- SAMRC/Wits Developmental Pathways for Health Research Unit (DPHRU), School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Tracy Snyman
- Department of Chemical Pathology, National Health Laboratory Service and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Andrew A Crawford
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Brian R Walker
- BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
- Institute of Genetic Medicine to Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Julia H Goedecke
- SAMRC/Wits Developmental Pathways for Health Research Unit (DPHRU), School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Non-communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa
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12
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Moran KM, González-Martínez LF, Delville Y. Lifelong enhancement of body mass from adolescent stress in male hamsters. Horm Behav 2021; 133:105004. [PMID: 34062278 DOI: 10.1016/j.yhbeh.2021.105004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/13/2021] [Accepted: 05/15/2021] [Indexed: 10/21/2022]
Abstract
In hamsters, exposure to stress in adulthood causes increased body weight. We addressed how social stress during puberty would impact food intake and body weight. Stressed hamsters started gaining significantly more weight than controls after only two days of stress exposure. Over a two-week period, stressed subjects gained 10% more weight and consumed more food than controls. At the end of the stress period, stressed hamsters collected nearly twice as many palatable sugar pellets from an arena than controls. Stressed subjects presented 15-20% more body fat in mesenteric, inguinal, and retroperitoneal fat pads. In order to assess the duration of these effects, we analyzed data from previous studies keeping hamsters for over two months past the stress period in puberty. Our analysis shows that stressed hamsters stopped gaining more weight after the stress period, but their body weights remained elevated for over two months, consistently weighing 10% more than their non-stressed counterparts. We also analyzed conditioning training data collected after the period of stress in late puberty and early adulthood (P56 to P70) that was part of the original studies. Training consisted of lever pressing for palatable food rewards. At these times, previously stressed hamsters retrieved similar numbers of food pellets from the conditioning chambers, suggesting no difference in appetite after the stress period. These data showing a long-lasting effect of stress on body weight may be relevant to studies on the ontogeny of lifelong obesity.
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Affiliation(s)
- Kevin M Moran
- Psychology Department, The University of Texas at Austin, Austin, TX 78712, USA.
| | | | - Yvon Delville
- Psychology Department, The University of Texas at Austin, Austin, TX 78712, USA
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13
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Kong CY, Wang CL, Niu KJ, Qi W. Prevalence of metabolic syndrome in patients with rheumatoid arthritis in eastern China-A hospital based study. Int J Rheum Dis 2021; 24:1121-1126. [PMID: 34080783 DOI: 10.1111/1756-185x.14148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 05/07/2021] [Accepted: 05/09/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE The purpose of this hospital clinic based study was to evaluate the potential risk factors associated with the prevalence of MetS in RA population. METHODS From January 2015 to October 2018, 717 patients with RA and 717 healthy controls who were treated or performed physical examination in Tianjin First Central Hospital were enrolled in this study. The basic disease diagnoses were recorded. A questionnaire was performed on all participants to assess the demographic details of the RA cohort. Moreover, laboratory indicators related to glucose and lipid metabolism in patients with RA were also detected. The potential risk factors for MetS were also analyzed. RESULTS The prevalence of MetS were 31.2% and 34.2% in case and control groups, respectively (P = .22). There were lower levels of HDL-C, obesity, TG, LDL-C and TC in case group than control group (all P < .05). The hypertension levels in healthy controls was decreased in compared with patients with RA (P < .05). Nevertheless, in patients with RA, complement 3 (OR: 1.02; 95% CI: 1.01-1.03, P = .007) and less glucocorticoids use (OR: 0.63, 95% CI: 0.39-0.99, P = .046) were associated with MetS. CONCLUSION The prevalence of MetS was not associated with RA. Complement 3 may be associated with the higher prevalence of MetS in patients with RA. Glucocorticoids treatment may be associated with MetS.
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Affiliation(s)
| | - Chang-Lei Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Kai-Jun Niu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China.,Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Wufang Qi
- Tianjin First Center Hospital, Tianjin, China
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14
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de Medeiros SF, Rodgers RJ, Norman RJ. Adipocyte and steroidogenic cell cross-talk in polycystic ovary syndrome. Hum Reprod Update 2021; 27:771-796. [PMID: 33764457 DOI: 10.1093/humupd/dmab004] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/08/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Metabolic and endocrine alterations in women with polycystic ovary syndrome (PCOS) affect adipose tissue mass and distribution. PCOS is characterised by hyperandrogenism, obesity and adipocyte dysfunction. Hyperandrogenism in PCOS drives dysfunctional adipocyte secretion of potentially harmful adipocytokines. Glucocorticoids and sex-steroids modulate adipocyte development and function. For their part, adipocyte products interact with adrenal and ovarian steroidogenic cells. Currently, the relationship between adipocyte and steroidogenic cells is not clear, and for these reasons, it is important to elucidate the interrelationship between these cells in women with and without PCOS. OBJECTIVE AND RATIONALE This comprehensive review aims to assess current knowledge regarding the interrelationship between adipocytes and adrenal and ovarian steroidogenic cells in animal models and humans with or without PCOS. SEARCH METHODS We searched for articles published in English and Portuguese in PubMed. Keywords were as follows: polycystic ovary syndrome, steroidogenesis, adrenal glands, theca cells, granulosa cells, adipocytes, adipocytokines, obesity, enzyme activation, and cytochrome P450 enzymes. We expanded the search into the references from the retrieved articles. OUTCOMES Glucocorticoids and sex-steroids modulate adipocyte differentiation and function. Dysfunctional adipocyte products play important roles in the metabolic and endocrine pathways in animals and women with PCOS. Most adipokines participate in the regulation of the hypothalamic-pituitary-adrenal and ovarian axes. In animal models of PCOS, hyperinsulinemia and poor fertility are common; various adipokines modulate ovarian steroidogenesis, depending on the species. Women with PCOS secrete unbalanced levels of adipocyte products, characterised by higher levels of leptin and lower levels of adiponectin. Leptin expression positively correlates with body mass index, waist/hip ratio and levels of total cholesterol, triglyceride, luteinising hormone, oestradiol and androgens. Leptin inhibits the production of oestradiol and, in granulosa cells, may modulate 17-hydroxylase and aromatase enzyme activities. Adiponectin levels negatively correlate with fat mass, body mass index, waist-hip ratio, glucose, insulin and triglycerides, and decrease androgen production by altering expression of luteinising hormone receptor, steroidogenic acute regulatory protein, cholesterol-side-chain cleavage enzyme and 17-hydroxylase. Resistin expression positively correlates with body mass index and testosterone, and promotes the expression of 17-hydroxylase enzyme in theca cells. The potential benefits of adipokines in the treatment of women with PCOS require more investigation. WIDER IMPLICATIONS The current data regarding the relationship between adipocyte products and steroidogenic cells are conflicting in animals and humans. Polycystic ovary syndrome is an excellent model to investigate the interrelationship among adipocyte and steroidogenic cells. Women with PCOS manifest some pathological conditions associated with hyperandrogenism and adipocyte products. In animals, cross-talk between cells may vary according to species, and the current review suggests opportunities to test new medications to prevent or even reverse several harmful sequelae of PCOS in humans. Further studies are required to investigate the possible therapeutic application of adipokines in women with obese and non-obese PCOS. Meanwhile, when appropriate, metformin use alone, or associated with flutamide, may be considered for therapeutic purposes.
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Affiliation(s)
- Sebastião Freitas de Medeiros
- Department of Gynecology and Obstetrics, Medical School, Federal University of Mato Grosso; and Tropical Institute of Reproductive Medicine,Cuiabá, MT, Brazil
| | - Raymond Joseph Rodgers
- Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia, Australia
| | - Robert John Norman
- Robinson Research Institute Adelaide Medical School, Adelaide, South Australia, Australia
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15
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Ruigrok SR, Abbink MR, Geertsema J, Kuindersma JE, Stöberl N, van der Beek EM, Lucassen PJ, Schipper L, Korosi A. Effects of Early-Life Stress, Postnatal Diet Modulation and Long-Term Western-Style Diet on Peripheral and Central Inflammatory Markers. Nutrients 2021; 13:288. [PMID: 33498469 PMCID: PMC7909521 DOI: 10.3390/nu13020288] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/15/2021] [Accepted: 01/17/2021] [Indexed: 01/06/2023] Open
Abstract
Early-life stress (ES) exposure increases the risk of developing obesity. Breastfeeding can markedly decrease this risk, and it is thought that the physical properties of the lipid droplets in human milk contribute to this benefit. A concept infant milk formula (IMF) has been developed that mimics these physical properties of human milk (Nuturis®, N-IMF). Previously, we have shown that N-IMF reduces, while ES increases, western-style diet (WSD)-induced fat accumulation in mice. Peripheral and central inflammation are considered to be important for obesity development. We therefore set out to test the effects of ES, Nuturis® and WSD on adipose tissue inflammatory gene expression and microglia in the arcuate nucleus of the hypothalamus. ES was induced in mice by limiting the nesting and bedding material from postnatal day (P) 2 to P9. Mice were fed a standard IMF (S-IMF) or N-IMF from P16 to P42, followed by a standard diet (STD) or WSD until P230. ES modulated adipose tissue inflammatory gene expression early in life, while N-IMF had lasting effects into adulthood. Centrally, ES led to a higher microglia density and more amoeboid microglia at P9. In adulthood, WSD increased the number of amoeboid microglia, and while ES exposure increased microglia coverage, Nuturis® reduced the numbers of amoeboid microglia upon the WSD challenge. These results highlight the impact of the early environment on central and peripheral inflammatory profiles, which may be key in the vulnerability to develop metabolic derangements later in life.
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Affiliation(s)
- Silvie R. Ruigrok
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; (S.R.R.); (M.R.A.); (J.G.); (J.E.K.); (N.S.); (P.J.L.)
| | - Maralinde R. Abbink
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; (S.R.R.); (M.R.A.); (J.G.); (J.E.K.); (N.S.); (P.J.L.)
| | - Jorine Geertsema
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; (S.R.R.); (M.R.A.); (J.G.); (J.E.K.); (N.S.); (P.J.L.)
| | - Jesse E. Kuindersma
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; (S.R.R.); (M.R.A.); (J.G.); (J.E.K.); (N.S.); (P.J.L.)
| | - Nina Stöberl
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; (S.R.R.); (M.R.A.); (J.G.); (J.E.K.); (N.S.); (P.J.L.)
| | - Eline M. van der Beek
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Paul J. Lucassen
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; (S.R.R.); (M.R.A.); (J.G.); (J.E.K.); (N.S.); (P.J.L.)
| | | | - Aniko Korosi
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; (S.R.R.); (M.R.A.); (J.G.); (J.E.K.); (N.S.); (P.J.L.)
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16
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Martel-Duguech L, Alonso-Jiménez A, Bascuñana H, Díaz-Manera J, Llauger J, Nuñez-Peralta C, Biagetti B, Montesinos P, Webb SM, Valassi E. Thigh Muscle Fat Infiltration Is Associated With Impaired Physical Performance Despite Remission in Cushing's Syndrome. J Clin Endocrinol Metab 2020; 105:5698174. [PMID: 31912154 DOI: 10.1210/clinem/dgz329] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/06/2020] [Indexed: 12/25/2022]
Abstract
CONTEXT Muscle weakness is common in patients with Cushing's syndrome (CS) and may persist after the resolution of hypercortisolism. Intramuscular fatty infiltration has been associated with the deterioration of muscle performance in several conditions. OBJECTIVES To quantify the degree of fatty infiltration in the thigh muscles of "cured" CS patients and evaluate the relationship between intramuscular fatty infiltration and physical performance. DESIGN This was a cross-sectional study. SETTING Tertiary referral center. PATIENTS Thirty-six women with CS in remission, and 36 controls matched for age, BMI, menopausal status, and level of physical activity. MAIN OUTCOME MEASURES We analyzed the percentage fat fraction (FF) of the thigh muscles in the anterior, posterior, and combined anterior and posterior compartments using MRI and 2-point Dixon sequence. We assessed muscle function and strength using the following tests: gait speed (GS), timed up and go (TUG), 30-second chair stand, and hand grip strength. RESULTS Fat fraction in all the compartments analyzed was increased in patients as compared with controls. The performance on TUG, 30-second chair stand, and GS was more impaired in CS patients versus controls. In patients, greater FF was negatively associated with performance on functional tests. Fat fraction in the combined anterior and posterior compartments predicted performance on TUG (ß 0.626, P < 0.000) and GS (ß -0.461, P = 0.007), after adjusting for age, BMI, menopausal status, and muscle mass. CONCLUSIONS Thigh muscle fatty infiltration is increased in "cured" CS patients and is associated with poorer muscle performance. Future studies are needed to establish therapeutic strategies to improve muscle weakness in these patients.
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Affiliation(s)
- Luciana Martel-Duguech
- IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain
- UAB, Bellaterra, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), Barcelona, Spain
| | - Alicia Alonso-Jiménez
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), Barcelona, Spain
- Neuromuscular Disorders Unit, Neurology Department, Hospital Sant Pau, Barcelona, Spain
| | | | - Jordi Díaz-Manera
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), Barcelona, Spain
- Neuromuscular Disorders Unit, Neurology Department, Hospital Sant Pau, Barcelona, Spain
| | - Jaume Llauger
- Radiology Department, Hospital Sant Pau, Barcelona, Spain
| | | | - Betina Biagetti
- Endocrinology Department, Hospital Vall d'Hebron, Barcelona, Spain
| | | | - Susan M Webb
- IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain
- UAB, Bellaterra, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), Barcelona, Spain
| | - Elena Valassi
- IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain
- UAB, Bellaterra, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), Barcelona, Spain
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Hay RE, Edwards A, Klein M, Hyland L, MacDonald D, Karatsoreos I, Hill MN, Abizaid A. Ghrelin Receptor Signaling Is Not Required for Glucocorticoid-Induced Obesity in Male Mice. Endocrinology 2020; 161:5636885. [PMID: 31748785 PMCID: PMC7445420 DOI: 10.1210/endocr/bqz023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 11/19/2019] [Indexed: 12/11/2022]
Abstract
Chronically elevated levels of glucocorticoids increase food intake, weight gain, and adiposity. Similarly, ghrelin, a gut-secreted hormone, is also associated with weight gain, adiposity, and increased feeding. Here we sought to determine if corticosterone-induced metabolic and behavioral changes require functional ghrelin receptors (GHSR). To do this, we treated male C57BL mice with chronic corticosterone (CORT) mixed in their drinking water for 28 days. Half of these mice received the GHSR antagonist JMV2959 via osmotic minipumps while treated with CORT. In a second experiment, we gave the same CORT protocol to mice with a targeted mutation to the GHSR or their wild-type littermates. As expected, CORT treatment increased food intake, weight gain, and adiposity, but contrary to expectations, mice treated with a GHSR receptor antagonist or GHSR knockout (KO) mice did not show attenuated food intake, weight gain, or adiposity in response to CORT. Similarly, the effects of CORT on the liver were the same or more pronounced in GHSR antagonist-treated and GHSR KO mice. Treatment with JMV2959 did attenuate the effects of chronic CORT on glycemic regulation as determined by the glucose tolerance test. Finally, disruption of GHSR signaling resulted in behavioral responses associated with social withdrawal, potentially due to neuroprotective effects of GHSR activation. In all, we propose that blocking GHSR signaling helps to moderate glucose concentrations when CORT levels are high, but blocking GHSR signaling does not prevent increased food intake, weight gain, or increased adiposity produced by chronic CORT.
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Affiliation(s)
- Rebecca E Hay
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - Alex Edwards
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - Marianne Klein
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - Lindsay Hyland
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - David MacDonald
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - Ilia Karatsoreos
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, US
| | - Matthew N Hill
- Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada
| | - Alfonso Abizaid
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
- Correspondence: Alfonso Abizaid, Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S5B6, Canada. E-mail:
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18
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Chronic corticosterone aggravates behavioral and neuronal symptomatology in a mouse model of alpha-synuclein pathology. Neurobiol Aging 2019; 83:11-20. [DOI: 10.1016/j.neurobiolaging.2019.08.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/20/2019] [Accepted: 08/09/2019] [Indexed: 02/06/2023]
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Mazurina NV, Ershova EV, Troshina EA, Senyushkina ES, Tyulpakov AN, Ioutsi VA. Fat tissue and adrenal function: mechanisms of mutual influence. MEDICAL COUNCIL 2019:70-77. [DOI: 10.21518/2079-701x-2019-4-70-77] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Affiliation(s)
- N. V. Mazurina
- Federal State Budgetary Institution National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation
| | - E. V. Ershova
- Federal State Budgetary Institution National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation
| | - E. A. Troshina
- Federal State Budgetary Institution National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation
| | - E. S. Senyushkina
- Federal State Budgetary Institution National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation
| | - A. N. Tyulpakov
- Federal State Budgetary Institution National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation
| | - V. A. Ioutsi
- Federal State Budgetary Institution National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation
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20
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Singleton JM, Garland T. Influence of corticosterone on growth, home-cage activity, wheel running, and aerobic capacity in house mice selectively bred for high voluntary wheel-running behavior. Physiol Behav 2019; 198:27-41. [DOI: 10.1016/j.physbeh.2018.10.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/20/2018] [Accepted: 10/02/2018] [Indexed: 12/19/2022]
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21
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Raghow R. Circadian rhythms of hormone secretion and obesity. World J Diabetes 2018; 9:195-198. [PMID: 30479685 PMCID: PMC6242724 DOI: 10.4239/wjd.v9.i11.195] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 10/08/2018] [Accepted: 10/24/2018] [Indexed: 02/05/2023] Open
Abstract
The adipose tissue homeostasis is profoundly affected by circadian rhythms of corticosteroid secretion and chronic loss of hormonal oscillations is associated with obesity. How adipose tissue differentially responds to pulsatile vs continuous presence of glucocorticoids is poorly defined. To address this question, Bahrami-Nejad et al studied differentiation of pre-adipocytes, containing endogenously tagged CCAAT/enhancer binding protein and peroxisome proliferator-activated receptor (PPAR) γ (key regulators of adipocyte differentiation), in response to corticosteroids that were delivered either in an oscillatory fashion or continuously. The authors show that the bi-stable state of differentiation of pre-adipocytes and adipocytes was regulated by a combination of fast and slow positive feedback networks, that determined unique threshold of PPARγ in these cells. Evidently, pre-adipocytes used the fast feedback loop to reject differentiation cues of oscillating pulses of glucocorticoids and failed to differentiate into fat cells. In contrast, when glucocorticoids were delivered continuously, precursor cells exploited the slow feedback loop to embark on a path of maximal differentiation. This differential differentiation response of pre-adipocytes to pulsatile vs continuous exposure to glucocorticoids was corroborated in vivo. Thus, mice receiving non-oscillating doses of exogenous glucocorticoids, for 21 d, elicited excessive accumulation of visceral and subcutaneous fat. These data shed new light on the mechanisms of obesity caused by putative misalignment of circadian secretion of glucocorticoids or their persistently high levels due to chronic stress or Cushing’s disease.
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Affiliation(s)
- Rajendra Raghow
- Department of Veterans Affairs Medical Center, Memphis, TN 38104, United States
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, United States
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22
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Song X, Jiao H, Zhao J, Wang X, Lin H. Dexamethasone and insulin stimulate ghrelin secretion of broilers in a different way. Gen Comp Endocrinol 2018; 268:14-21. [PMID: 30016627 DOI: 10.1016/j.ygcen.2018.07.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/06/2018] [Accepted: 07/13/2018] [Indexed: 12/27/2022]
Abstract
Ghrelin is one of the most important appetite regulating peptides, involved in the regulation of energy homeostasis. The role of ghrelin on the appetite and fat metabolism in chickens is different from that of ghrelin in mammals. Glucocorticoids and insulin are important hormones and work differently in energy regulation of body. In this study, the effects of dexamethasone (DEX, 2.0 mg/kg BW), subcutaneous insulin injection (40 µg/kg BW), and glucose load on ghrelin secretion and expression were determined in broilers. DEX treatment increased circulating ghrelin concentration in broiler fed with either a low-energy diet (11.05 MJ/kg of metabolizable energy) or a high-energy diet (14.44 MJ/kg of metabolizable energy). The expression levels of ghrelin were increased while both ghrelin and its receptor GHS-R1a expression levels were stimulated by DEX. A single subcutaneous insulin injection (40 µg/kg BW) or oral glucose infusion (2 g/kg BW) rise circulating ghrelin level. Ghrelin expression in the proventriculus was increased by insulin treatment but unchanged by glucose load. DEX had no detectable influence on ghrelin and GHS-R1a expression in the hypohtalamus, whereas insulin suppressed their expression. In conclusion, both insulin and glucocorticoid stimulate ghrelin secretion in chickens, in contrast to mammals. Glucocorticoids evoke peripheral ghrelin/GHS-R1a system while insulin increases peripheral ghrelin expression and suppress the activation of central ghrelin/GHS-R1a system. The result suggests that ghrelin involved in the modulating network of energy homeostasis in concert with glucocorticoids and insulin.
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Affiliation(s)
- Xixi Song
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, No. 61 Daizong Street, Tai'an 271018, PR China
| | - Hongchao Jiao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, No. 61 Daizong Street, Tai'an 271018, PR China
| | - Jingpeng Zhao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, No. 61 Daizong Street, Tai'an 271018, PR China
| | - Xiaojuan Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, No. 61 Daizong Street, Tai'an 271018, PR China
| | - Hai Lin
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, No. 61 Daizong Street, Tai'an 271018, PR China.
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23
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Conyersm FG, Langevin HM, Badger GJ, Mehta DH. Identifying Stress Landscapes in Boston Neighborhoods. Glob Adv Health Med 2018; 7:2164956118803058. [PMID: 30349761 PMCID: PMC6195011 DOI: 10.1177/2164956118803058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 08/17/2018] [Indexed: 11/17/2022] Open
Abstract
Background Chronic stress plays a role in the development of health disparities. However, the relationship between neighborhood stressors and stress-related health problems and behaviors is unknown. In the city of Boston, Massachusetts, 3 neighborhoods, while within a 3 mile radius, have widely divergent life expectancies. This work aims to investigate and compare perceived neighborhood-level stressors, stress-related negative behaviors, and stress-related health problems in these neighborhoods. Methods Three hundred twenty-six participants were surveyed from the neighborhoods. Participants were asked to rate (1) 27 neighborhood stressors, (2) 16 stress-related negative behaviors, and (3) 13 stress-related health problems using a 1 to 5 Likert-type scale. Differences in responses between neighborhoods were analyzed using Kruskal–Wallis and χ2 tests. Results The highest neighborhood stressors overall were related to finance, unequal treatment, and unsafe bike/pedestrian access. The highest stress-related health problems were related to substance abuse and obesity, and the largest stress-related behaviors were related to poor diet, intolerance, and aggressive driving. There were significant differences across neighborhoods (P < .05) for 18 of the 27 neighborhood stressors, 8 of the 10 stress-related health problems, and 12 of the 15 stress-related behaviors. Conclusions There is marked contrast in stress landscapes between the 3 neighborhoods in Boston despite their geographical proximity. This finding potentially serves as an explanation for the drastic differences in health outcomes, even though these neighborhoods are equidistant from academic medical centers. Strategies for improving the health of individuals should incorporate the unique stressors at the neighborhood level. Further research is needed to investigate how specifically neighborhood stressors influence the health of residents, thereby informing what policy interventions might be useful.
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Affiliation(s)
| | - Helene M Langevin
- Harvard Medical School, Boston, Massachusetts, USA.,Osher Center for Integrative Medicine, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Gary J Badger
- Department of Medical Biostatistics, University of Vermont, Burlington, Vermont, USA
| | - Darshan H Mehta
- Harvard Medical School, Boston, Massachusetts, USA.,Osher Center for Integrative Medicine, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Benson-Henry Institute for Mind Body Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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Sadie-Van Gijsen H. Adipocyte biology: It is time to upgrade to a new model. J Cell Physiol 2018; 234:2399-2425. [PMID: 30192004 DOI: 10.1002/jcp.27266] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 07/25/2018] [Indexed: 12/15/2022]
Abstract
Globally, the obesity pandemic is profoundly affecting quality of life and economic productivity, but efforts to address this, especially on a pharmacological level, have generally proven unsuccessful to date, serving as a stark demonstration that our understanding of adipocyte biology and pathophysiology is incomplete. To deliver better insight into adipocyte function and obesity, we need improved adipocyte models with a high degree of fidelity in representing the in vivo state and with a diverse range of experimental applications. Adipocyte cell lines, especially 3T3-L1 cells, have been used extensively over many years, but these are limited in terms of relevance and versatility. In this review, I propose that primary adipose-derived stromal/stem cells (ASCs) present a superior model with which to study adipocyte biology ex vivo. In particular, ASCs afford us the opportunity to study adipocytes from different, functionally distinct, adipose depots and to investigate, by means of in vivo/ex vivo studies, the effects of many different physiological and pathophysiological factors, such as age, body weight, hormonal status, diet and nutraceuticals, as well as disease and pharmacological treatments, on the biology of adipocytes and their precursors. This study will give an overview of the characteristics of ASCs and published studies utilizing ASCs, to highlight the areas where our knowledge is lacking. More comprehensive studies in primary ASCs will contribute to an improved understanding of adipose tissue, in healthy and dysfunctional states, which will enhance our efforts to more successfully manage and treat obesity.
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Affiliation(s)
- Hanél Sadie-Van Gijsen
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa.,Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa
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25
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Douglas HD, Kitaysky AS, Kitaiskaia EV. Odor is linked to adrenocortical function and male ornament size in a colonial seabird. Behav Ecol 2018. [DOI: 10.1093/beheco/ary032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Hector D Douglas
- Institute of Marine Science, University of Alaska Fairbanks, Koyukuk Drive, Fairbanks, AK, USA
- Fairbanks, AK, USA
| | - Alexander S Kitaysky
- Institute of Arctic Biology, University of Alaska Fairbanks, Koyukuk Drive, Fairbanks, AK, USA
| | - Evgenia V Kitaiskaia
- Institute of Arctic Biology, University of Alaska Fairbanks, Koyukuk Drive, Fairbanks, AK, USA
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26
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Strait RB, Slattery MJ, Carrel AL, Eickhoff J, Allen DB. Salivary Cortisol Does Not Correlate with Metabolic Syndrome Markers or Subjective Stress in Overweight Children. JOURNAL OF CHILDHOOD OBESITY 2018; 3:8. [PMID: 29998225 PMCID: PMC6037313 DOI: 10.21767/2572-5394.100048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Being overweight is a risk factor for metabolic syndrome in children, but not all overweight children develop metabolic syndrome. Cortisol excess from chronic psychological stress has been proposed as an independent risk factor for metabolic syndrome in this already at-risk population. The present study assesses the relationship of biochemical and body composition radiographic markers of metabolic syndrome to salivary cortisol and self-report of chronic psychological stress in a cohort of overweight children. METHODS This cross-sectional study took place in a multi-disciplinary pediatric obesity clinic at a tertiary care hospital, and involved fifteen children with BMI at or above the 85th percentile for age and sex, 10 of whom provided salivary cortisol samples. The main outcomes measured were salivary bedtime cortisol, first-waking cortisol, and cortisol awakening response (CAR-the rise in cortisol in the first half hour after waking); fasting serum triglycerides, HDL cholesterol, glucose and insulin for HOMA-IR; the ratio of abdominal fat to total body fat by DXA scan; and scores of validated stress and bullying questionnaires (PANAS-C, PSS, and SEC-Q). RESULTS In this pilot study, no correlation was found between salivary cortisol measures and questionnaire scores of subjective stress or bullying, and no correlation was found between any of these measures and markers of metabolic syndrome (dyslipidemia, insulin resistance, increased abdominal fat). CONCLUSIONS These results suggest that measures of psychological stress, whether biochemical or subjective, do not appear to predict risk of metabolic syndrome in overweight children. While ease of collection and demonstrated utility both in detection of pediatric Cushing disease and in adult psychological research make salivary cortisol assessment an attractive clinical tool, further investigation into the value of salivary measures in pediatric stress research is needed.
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Affiliation(s)
- Robert B. Strait
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, H4-436, Madison WI, 53792
| | - Marcia J. Slattery
- Department of Child and Adolescent Psychiatry, University of Wisconsin School of Medicine and Public Health, 6001 Research Park Blvd, Madison, WI 53719
| | - Aaron L. Carrel
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, H4-436, Madison WI, 53792
| | - Jens Eickhoff
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, H4-436, Madison WI, 53792
| | - David B. Allen
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, H4-436, Madison WI, 53792
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27
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Bahrami-Nejad Z, Zhao ML, Tholen S, Hunerdosse D, Tkach KE, van Schie S, Chung M, Teruel MN. A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation. Cell Metab 2018; 27:854-868.e8. [PMID: 29617644 PMCID: PMC5889123 DOI: 10.1016/j.cmet.2018.03.012] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 01/26/2018] [Accepted: 03/17/2018] [Indexed: 12/12/2022]
Abstract
Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern correlates with obesity in humans, raising the intriguing question of how hormone secretion dynamics affect adipocyte differentiation. Using live, single-cell imaging of the key adipogenic transcription factors CEBPB and PPARG, endogenously tagged with fluorescent proteins, we show that pulsatile circadian hormone stimuli are rejected by the adipocyte differentiation control system. In striking contrast, equally strong persistent signals trigger maximal differentiation. We identify the mechanism of how hormone oscillations are filtered as a combination of slow and fast positive feedback centered on PPARG. Furthermore, we confirm in mice that flattening of daily glucocorticoid oscillations significantly increases the mass of subcutaneous and visceral fat pads. Together, our study provides a molecular mechanism for why stress, Cushing's disease, and other conditions for which glucocorticoid secretion loses its pulsatility may lead to obesity.
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Affiliation(s)
- Zahra Bahrami-Nejad
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Michael L Zhao
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Stefan Tholen
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Devon Hunerdosse
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Karen E Tkach
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Sabine van Schie
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Mingyu Chung
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Mary N Teruel
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
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28
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Intrauterine growth restriction combined with a maternal high-fat diet increased adiposity and serum corticosterone levels in adult rat offspring. J Dev Orig Health Dis 2018; 9:315-328. [DOI: 10.1017/s2040174418000016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
AbstractIntrauterine growth restriction (IUGR) and fetal exposure to a maternal high-fat diet (HFD) independently increase the risk of developing obesity in adulthood. Excess glucocorticoids increase obesity. We hypothesized that surgically induced IUGR combined with an HFD would increase adiposity and glucocorticoids more than in non-IUGR offspring combined with the same HFD, findings that would persist despite weaning to a regular diet. Non-IUGR (N) and IUGR (I) rat offspring from dams fed either regular rat chow (R) or an HFD (H) were weaned to either a regular rat chow or an HFD. For non-IUGR and IUGR rats, this study design resulted in three diet groups: offspring from dams fed a regular diet and weaned to a regular diet (NRR and IRR), offspring rats from dams fed an HFD and weaned to a regular diet (NHR and IHR) and offspring from dams fed an HFD and weaned to an HFD (NHH and IHH). Magnetic resonance imaging or fasting visceral and subcutaneous adipose tissue collection occurred at postnatal day 60. IHH male rats had greater adiposity than NHH males, findings that were only partly normalized by weaning to a regular chow. IHH male rats had a 10-fold increase in serum corticosterone levels. IHH female rats had increased adiposity and serum triglycerides. We conclude that IUGR combined with an HFD throughout life increased adiposity, glucocorticoids and triglycerides in a sex-specific manner. Our data suggest that one mechanism through which the perinatal environment programs increased adiposity in IHH male rats may be via increased systemic glucocorticoids.
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29
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de Kloet AD, Herman JP. Fat-brain connections: Adipocyte glucocorticoid control of stress and metabolism. Front Neuroendocrinol 2018; 48:50-57. [PMID: 29042142 DOI: 10.1016/j.yfrne.2017.10.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/12/2017] [Accepted: 10/13/2017] [Indexed: 01/08/2023]
Abstract
Glucocorticoids act via multiple mechanisms to mobilize energy for maintenance and restoration of homeostasis. In adipose tissue, glucocorticoids can promote lipolysis and facilitate adipocyte differentiation/growth, serving both energy-mobilizing and restorative processes during negative energy balance. Recent data suggest that adipose-dependent feedback may also be involved in regulation of stress responses. Adipocyte glucocorticoid receptor (GR) deletion causes increased HPA axis stress reactivity, due to a loss of negative feedback signals into the CNS. The fat-to-brain signal may be mediated by neuronal mechanisms, release of adipokines or increased lipolysis. The ability of adipose GRs to inhibit psychogenic as well as metabolic stress responses suggests that (1) feedback regulation of the HPA axis occurs across multiple bodily compartments, and (2) fat tissue integrates psychogenic stress signals. These studies support a link between stress biology and energy metabolism, a connection that has clear relevance for numerous disease states and their comorbidities.
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Affiliation(s)
- Annette D de Kloet
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32611, United States
| | - James P Herman
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, United States.
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30
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31
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Roerink SHPP, Wagenmakers MAEM, Langenhuijsen JF, Ballak DB, Rooijackers HMM, d'Ancona FC, van Dielen FM, Smit JWA, Plantinga TS, Netea-Maier RT, Hermus ARMM. Increased Adipocyte Size, Macrophage Infiltration, and Adverse Local Adipokine Profile in Perirenal Fat in Cushing's Syndrome. Obesity (Silver Spring) 2017; 25:1369-1374. [PMID: 28594137 DOI: 10.1002/oby.21887] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 04/19/2017] [Accepted: 04/27/2017] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To analyze changes in fat cell size, macrophage infiltration, and local adipose tissue adipokine profiles in different fat depots in patients with active Cushing's syndrome. METHODS Subcutaneous (SC) and perirenal (PR) adipose tissue of 10 patients with Cushing's syndrome was compared to adipose tissue of 10 gender-, age-, and BMI-matched controls with regard to adipocyte size determined by digital image analysis on hematoxylin and eosin stainings, macrophage infiltration determined by digital image analysis on CD68 stainings, and adipose tissue leptin and adiponectin levels using fluorescent bead immunoassays and ELISA techniques. RESULTS Compared to the controls, mean adipocyte size was larger in PR adipose tissue in patients. The percentage of macrophage infiltration of the PR adipose tissue and PR adipose tissue lysate leptin levels were higher and adiponectin levels were lower in SC and PR adipose tissue lysates in patients. The adiponectin levels were also lower in the SC adipose tissue supernatants of patients. Associations were found between the severity of hypercortisolism and PR adipocyte size. CONCLUSIONS Cushing's syndrome is associated with hypertrophy of PR adipocytes and a higher percentage of macrophage infiltration in PR adipose tissue. These changes are associated with an adverse local adipokine profile.
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Affiliation(s)
- Sean H P P Roerink
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Margreet A E M Wagenmakers
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Dov B Ballak
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Hanne M M Rooijackers
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Frank C d'Ancona
- Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - François M van Dielen
- Department of General Surgery, Maxima Medical Center Eindhoven, Eindhoven, the Netherlands
| | - Jan W A Smit
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Theo S Plantinga
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Romana T Netea-Maier
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Ad R M M Hermus
- Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands
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Jaggar M, Weisstaub N, Gingrich JA, Vaidya VA. 5-HT 2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress. Neurobiol Stress 2017. [PMID: 28626787 PMCID: PMC5470573 DOI: 10.1016/j.ynstr.2017.06.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT2A receptor knockout (5-HT2A−/−) and wild-type mice of both sexes. While 5-HT2A−/− male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2A−/− female mice with a hyperlipidemic baseline phenotype. 5-HT2A−/− male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2), trophic factors (Bdnf, Igf1) and immediate early genes (IEGs) (Arc, Fos, Fosb, Egr1-4) in the PFC and hippocampus were altered in 5-HT2A−/− mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic.
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Affiliation(s)
- Minal Jaggar
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Noelia Weisstaub
- Department of Physiology, Faculty of Medicine, University of Buenos Aires, Argentina
| | - Jay A Gingrich
- Department of Psychiatry, Columbia University, New York, United States
| | - Vidita A Vaidya
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
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33
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Role of addiction and stress neurobiology on food intake and obesity. Biol Psychol 2017; 131:5-13. [PMID: 28479142 DOI: 10.1016/j.biopsycho.2017.05.001] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 02/20/2017] [Accepted: 05/01/2017] [Indexed: 02/07/2023]
Abstract
The US remains at the forefront of a global obesity epidemic with a significant negative impact on public health. While it is well known that a balance between energy intake and expenditure is homeostatically regulated to control weight, growing evidence points to multifactorial social, neurobehavioral and metabolic determinants of food intake that influence obesity risk. This review presents factors such as the ubiquitous presence of rewarding foods in the environment and increased salience of such foods that stimulate brain reward motivation and stress circuits to influence eating behaviors. These rewarding foods via conditioned and reinforcing effects stimulate not only metabolic, but also stress hormones, that, in turn, hijack the brain emotional (limbic) and motivational (striatal) pathways, to promote food craving and excessive food intake. Furthermore, the impact of high levels of stress and trauma and altered metabolic environment (e.g. higher weight, altered insulin sensitivity) on prefrontal cortical self-control processes that regulate emotional, motivational and visceral homeostatic mechanisms of food intake and obesity risk are also discussed. A heuristic framework is presented in which the interactive dynamic effects of neurobehavioral adaptations in metabolic, motivation and stress neurobiology may further support food craving, excessive food intake and weight gain in a complex feed-forward manner. Implications of such adaptations in brain addictive-motivational and stress pathways and their effects on excessive food intake and weight gain are discussed to highlight key questions that requires future research attention in order to better understand and address the growing obesity epidemic.
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Razzoli M, Pearson C, Crow S, Bartolomucci A. Stress, overeating, and obesity: Insights from human studies and preclinical models. Neurosci Biobehav Rev 2017; 76:154-162. [PMID: 28292531 PMCID: PMC5403578 DOI: 10.1016/j.neubiorev.2017.01.026] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 01/06/2017] [Accepted: 01/21/2017] [Indexed: 12/22/2022]
Abstract
Eating disorders and obesity have become predominant in human society. Their association to modern lifestyle, encompassing calorie-rich diets, psychological stress, and comorbidity with major diseases are well documented. Unfortunately the biological basis remains elusive and the pharmacological treatment inadequate, in part due to the limited availability of valid animal models. Human research on binge eating disorder (BED) proves a strong link between stress exposure and bingeing: state-levels of stress and negative affect are linked to binge eating in individuals with BED both in laboratory settings and the natural environment. Similarly, classical animal models of BED reveal an association between acute exposure to stressors and binging but they are often associated with unchanged or decreased body weight, thus reflecting a negative energy balance, which is uncommon in humans where most commonly BED is associated with excessive or unstable body weight gain. Recent mouse models of subordination stress induce spontaneous binging and hyperphagia, altogether more closely mimicking the behavioral and metabolic features of human BED. Therefore the translational relevance of subordination stress models could facilitate the identification of the neurobiological basis of BED and obesity-associated disease and inform on the development of innovative therapies.
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Affiliation(s)
- Maria Razzoli
- Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
| | - Carolyn Pearson
- Department of Psychiatry, University of Minnesota, 2450 Riverside Avenue, Minneapolis, MN 55454, USA
| | - Scott Crow
- Department of Psychiatry, University of Minnesota, 2450 Riverside Avenue, Minneapolis, MN 55454, USA; The Emily Program, 2265 Como Avenue, St. Paul, MN 55108, USA
| | - Alessandro Bartolomucci
- Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA.
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35
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Miller AL, Kaciroti N, Sturza J, Retzloff L, Rosenblum K, Vazquez DM, Lumeng JC. Associations between stress biology indicators and overweight across toddlerhood. Psychoneuroendocrinology 2017; 79:98-106. [PMID: 28273588 PMCID: PMC5367941 DOI: 10.1016/j.psyneuen.2017.02.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 02/11/2017] [Accepted: 02/12/2017] [Indexed: 12/21/2022]
Abstract
Biological stress responses are proposed as a pathway through which stress exposure can "get under the skin" and lead to health problems, specifically obesity. Yet, it is not clear when such associations may emerge or whether they are bidirectional. Cortisol and salivary alpha amylase (sAA) were considered indicators of the biological stress response. We tested the longitudinal association between cortisol and sAA and weight in 215 low-income children at ages 21, 27, and 33 months (52% male; 46% non-Hispanic white). sAA and cortisol intercept and slope (representing morning level and rate of change across the day) were calculated for each age point using random effect models. Children were weighed and length measured and categorized as overweight versus normal weight (overweight defined as weight-for-length z-score ≥85th percentile for age and sex). Cross-lagged models stratified by sex and controlling for birthweight z-score tested the concurrent and cross-lagged associations between each of 4 indices of stress biology individually (cortisol and sAA intercept and slope) and overweight. Overweight status was correlated across time. Cortisol and sAA were correlated across occasions of measurement, though somewhat less strongly in boys. There were no concurrent associations between stress indicators and overweight. sAA at 27 months predicted greater risk of overweight at 33 months in girls, such that both lower sAA intercept and more rapidly increasing sAA at 27 months predicted greater risk of overweight at 33 months (β=-0.64, p<0.05 and β=1.09, p<0.05, respectively). For boys only, overweight at 21 months predicted lower sAA intercept at 27 months (β=-0.35, p<0.05). Findings suggest that longitudinal associations of stress biology and weight status may be present only on a limited basis very early in the lifespan.
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Affiliation(s)
- Alison L Miller
- Center for Human Growth and Development, University of Michigan, United States; Department of Health Behavior and Health Education, University of Michigan School of Public Health,United States.
| | - Niko Kaciroti
- Center for Human Growth and Development, University of Michigan, United States; Department of Biostatistics, University of Michigan School of Public Health, United States
| | - Julie Sturza
- Center for Human Growth and Development, University of Michigan, United States
| | - Lauren Retzloff
- Center for Human Growth and Development, University of Michigan, United States
| | - Katherine Rosenblum
- Center for Human Growth and Development, University of Michigan, United States; Department of Psychiatry, University of Michigan Medical School, United States
| | - Delia M Vazquez
- Center for Human Growth and Development, University of Michigan, United States; Department of Biostatistics, University of Michigan School of Public Health, United States; Department of Pediatrics, University of Michigan Medical School, United States
| | - Julie C Lumeng
- Center for Human Growth and Development, University of Michigan, United States; Department of Pediatrics, University of Michigan Medical School, United States; Department of Nutritional Sciences, University of Michigan School of Public Health, United States
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36
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Lattin CR, Pechenenko AV, Carson RE. Experimentally reducing corticosterone mitigates rapid captivity effects on behavior, but not body composition, in a wild bird. Horm Behav 2017; 89:121-129. [PMID: 28065712 PMCID: PMC5359069 DOI: 10.1016/j.yhbeh.2016.12.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 12/23/2016] [Accepted: 12/29/2016] [Indexed: 01/02/2023]
Abstract
Wild animals and captives display physiological and behavioral differences, and it has been hypothesized, but rarely tested, that these differences are caused by sustained elevation of the hormone corticosterone. We used repeated computed tomography (CT) imaging to examine body composition changes in breeding male and female wild house sparrows (Passer domesticus; n=20) in response to two weeks of captivity, and assessed behavioral changes using video recordings. Half of the birds received the drug mitotane, which significantly decreased stress-induced corticosterone titers compared to controls. Based on the CT images, fat volumes increased, and pectoralis muscle density and heart and testes volumes decreased, over the two weeks of captivity in both groups of birds. However, beak-wiping, a behavior that can indicate anxiety and aggression, showed increased occurrence in controls compared to mitotane-treated birds. While our results do not support the hypothesis that these body composition changes were primarily driven by stress-induced corticosterone, our data suggest that experimentally reducing stress-induced corticosterone may mitigate some captivity-induced behavioral changes. Broadly, our results emphasize that researchers should take behavioral and physiological differences between free-living animals and captives into consideration when designing studies and interpreting results. Further, time in captivity should be minimized when birds will be reintroduced back to the wild.
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Affiliation(s)
- Christine R Lattin
- Department of Radiology and Biomedical Imaging, Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT 06520-8048, United States.
| | - Anita V Pechenenko
- Department of Radiology and Biomedical Imaging, Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT 06520-8048, United States
| | - Richard E Carson
- Department of Radiology and Biomedical Imaging, Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT 06520-8048, United States
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Jackson SE, Kirschbaum C, Steptoe A. Hair cortisol and adiposity in a population-based sample of 2,527 men and women aged 54 to 87 years. Obesity (Silver Spring) 2017; 25:539-544. [PMID: 28229550 PMCID: PMC5324577 DOI: 10.1002/oby.21733] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 10/20/2016] [Accepted: 10/25/2016] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Chronic cortisol exposure is hypothesized to contribute to obesity. This study examined associations between hair cortisol concentrations, a novel indicator of long-term cortisol exposure, and adiposity in a large population-based sample. METHODS Data were from 2,527 men and women aged 54 and older (98% white British) participating in the English Longitudinal Study of Ageing. Hair cortisol concentrations were determined from the scalp-nearest 2 cm hair segment, and height, weight, and waist circumference were objectively measured. Covariates included age, sex, socioeconomic status, smoking status, diabetes, and arthritis. RESULTS In cross-sectional analyses, hair cortisol concentrations were positively correlated with weight (r = 0.102, P < 0.001), BMI (r = 0.101, P < 0.001), and waist circumference (r = 0.082, P = 0.001) and were significantly elevated in participants with obesity (BMI ≥30 kg/m2 ) (F = 6.58, P = 0.001) and raised waist circumference (≥102 cm in men, ≥88 cm in women) (F = 4.87, P = 0.027). Hair cortisol levels were also positively associated with the persistence of obesity (F = 12.70, P < 0.001), evaluated in retrospect over 4 years. CONCLUSIONS Chronic exposure to elevated cortisol concentrations, assessed in hair, is associated with markers of adiposity and with the persistence of obesity over time.
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Affiliation(s)
- Sarah E. Jackson
- Department of Epidemiology and Public HealthUniversity College LondonLondonUK
| | | | - Andrew Steptoe
- Department of Epidemiology and Public HealthUniversity College LondonLondonUK
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Stress-related and basic determinants of hair cortisol in humans: A meta-analysis. Psychoneuroendocrinology 2017; 77:261-274. [PMID: 28135674 DOI: 10.1016/j.psyneuen.2016.12.017] [Citation(s) in RCA: 609] [Impact Index Per Article: 76.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/25/2016] [Accepted: 12/21/2016] [Indexed: 01/02/2023]
Abstract
The analysis of hair cortisol concentrations (HCC) is a relatively new strategy to measure long-term cumulative cortisol levels, which is increasingly used in psychoneuroendocrinological research. Here, we conduct a first comprehensive meta-analysis of HCC research based on aggregated data from a total of 124 (sub)samples (66 independent studies; total N=10,289). We seek to answer two central questions: (i) Which covariates and basic features of HCC need to be considered in future research? (ii) What are the main determinants of HCC in terms of chronic stress exposure and mental health? Concerning basic characteristics, our findings identify several covariates to be considered (age, sex, hair washing frequency, hair treatment, oral contraceptive use), confirm a decline of HCC from the first to the second proximal 3cm hair segment, and show positive associations between HCC and short-term salivary cortisol measures. Regarding chronic stress, we show that stress-exposed groups on a whole exhibit 22% increased HCC. This long-term cortisol hypersecretion emerges particularly when stress is still ongoing at the time of study (+43% HCC) but is not present in conditions of past/absent stress (-9% HCC, n.s.). We also report evidence for 17%-reduced HCC in anxiety disorders, such as PTSD. Interestingly, no consistent associations with mood disorders and self-reports of perceived stress, depressiveness or social support are found. However, our findings reveal positive associations of HCC with stress-related anthropometric (body mass index, waist-to-hip ratio) and hemodynamic measures (systolic blood pressure). These meta-analytic results are discussed in the light of their practical implications and important areas for future inquiry are outlined.
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García-Luna C, Soberanes-Chávez P, de Gortari P. Prepuberal light phase feeding induces neuroendocrine alterations in adult rats. J Endocrinol 2017; 232:15-28. [PMID: 27729464 DOI: 10.1530/joe-16-0402] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 10/11/2016] [Indexed: 01/28/2023]
Abstract
Feeding patterns are important factors in obesity evolvement. Time-restricted feeding schedules (tRF) during resting phase change energy homeostasis regulation, disrupting the circadian release of metabolism-regulating hormones, such as leptin, insulin and corticosterone and promoting body weight gain. Thyroid (HPT) and adrenal (HPA) axes exhibit a circadian regulation and are involved in energy expenditure, thus studying their parameters in tRF paradigms will elucidate their role in energy homeostasis impairments under such conditions. As tRF in young animals is poorly studied, we subjected prepuberal rats to a tRF either in light (LPF) or in darkness phase (DPF) and analyzed HPT and HPA response when they reach adulthood, as well as their arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei neurons' sensitivity to leptin in subsets of 10-week-old animals after fasting and with i.p. leptin treatment. LPF group showed high body weight and food intake, along with increased visceral fat pads, corticosterone, leptin and insulin serum levels, whereas circulating T4 decreased. HPA axis hyperactivity was demonstrated by their high PVN Crf mRNA expression; the blunted activity of HPT axis, by the decreased hypophysiotropic PVN Trh mRNA expression. Trh impaired expression to the positive energy balance in LPF, accounted for their ARC leptin resistance, evinced by an increased Npy and Socs3 mRNA expression. We concluded that the hyperphagia of prepuberal LPF animals could account for the HPA axis hyperactivity and for the HPT blocked function due to the altered ARC leptin signaling and impaired NPY regulation on PVN TRH neurons.
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Affiliation(s)
- C García-Luna
- Department of Neurosciences ResearchMolecular Neurophysiology Laboratory, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City, Mexico
| | - P Soberanes-Chávez
- Department of Neurosciences ResearchMolecular Neurophysiology Laboratory, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City, Mexico
| | - P de Gortari
- Department of Neurosciences ResearchMolecular Neurophysiology Laboratory, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City, Mexico
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Kokavec A. Migraine: A disorder of metabolism? Med Hypotheses 2016; 97:117-130. [PMID: 27876120 DOI: 10.1016/j.mehy.2016.10.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 10/23/2016] [Accepted: 10/31/2016] [Indexed: 02/08/2023]
Abstract
The treatment and prevention of migraine within the last decade has become largely pharmacological. While there is little doubt that the advent of drugs (e.g. triptans) has helped many migraine sufferers to lead a normal life, there is still little knowledge with respect to the factors responsible for precipitating a migraine attack. Evidence from biochemical and behavioural studies from a number of disciplines is integrated to put forward the proposal that migraine is part of a cascade of events, which together act to protect the organism when confronted by a metabolic challenge.
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Affiliation(s)
- Anna Kokavec
- University of New England, School of Health, Armidale, NSW 2350, United States.
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Wu T, Jiang J, Yang L, Li H, Zhang W, Chen Y, Zhao B, Kong B, Lu P, Zhao Z, Zhu J, Fu Z. Timing of glucocorticoid administration determines severity of lipid metabolism and behavioral effects in rats. Chronobiol Int 2016; 34:78-92. [PMID: 27791398 DOI: 10.1080/07420528.2016.1238831] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Glucocorticoids (GCs) are a group of steroid hormones secreted by the adrenal glands in circadian cycles, and the dysregulation of GC signaling has been suggested to cause metabolic syndrome. Even though prolonged GC exposure is associated with serious side effects such as metabolic syndrome and central nervous system disorders, the use of GCs in anti-inflammatory and immunosuppressive therapies has been continuously rising. Meanwhile, the exact mechanisms by which GCs can influence the lipid metabolism as well as behavior and how they are affected by time remain unknown. In this study, the effects of two different long-term GC dosing regimens on lipid metabolism and behavior were investigated. Male Wistar rats received daily administrations of the GC dexamethasone sodium phosphate (DEX, 0.5 mg/kg body weight) at either ZT0 (Dex0) or ZT12 (Dex12). After 6 weeks of treatment, DEX-treated rats, especially those treated at ZT0, had higher hepatic lipid accumulation and serum triglyceride levels and less locomotor activity than did control rats. In addition, serum levels of corticosterone, 5-hydroxy tryptamine and norepinephrine were decreased in the Dex0 group but not in the Dex12 group compared to the control group. Furthermore, quantitative real-time polymerase chain reaction analysis indicated that the chronic administration of GCs at ZT0 upregulated genes related to glycolysis and lipid synthesis and downregulated genes related to fatty acid β-oxidation in the liver more remarkably than administration at ZT12. Both DEX-treated groups displayed severely altered expression patterns of the core clock genes Bmal1 and Per2 in the liver and in fat. In addition, the expression of glutamate aspartate transporter, glial fibrillary acidic protein and glutamate transporter-1, astrocyte-related genes important for maintaining nervous system functions, was drastically decreased in the hippocampus of DEX-treated rats, especially when DEX was given at ZT0. In conclusion, our findings confirm that the severity of side effects, indicated by altered lipid metabolism and behavioral activity, depends on the timing of GC administration and is associated with the degree of glucocorticoid receptor dysfunction after dosing at disparate time points.
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Affiliation(s)
- Tao Wu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Jianguo Jiang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Luna Yang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Haifeng Li
- b Children's Hospital , Zhejiang University School of Medicine , Zhejiang , China
| | - Wanjing Zhang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Yangyang Chen
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Binggong Zhao
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Boda Kong
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Ping Lu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Zhenzhen Zhao
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Jiawei Zhu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Zhengwei Fu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
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Lacey RE, Kumari M, Sacker A, Stafford M, Kuh D, McMunn A. Work-Family Life Courses and Metabolic Markers in the MRC National Survey of Health and Development. PLoS One 2016; 11:e0161923. [PMID: 27563726 PMCID: PMC5001719 DOI: 10.1371/journal.pone.0161923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 08/15/2016] [Indexed: 11/18/2022] Open
Abstract
The aim was to investigate whether the combined work-family life courses of British men and women were associated with differences in metabolic markers-waist circumference, blood pressure, high density lipoprotein cholesterol, triglycerides, and glycated haemoglobin-in mid-life. We used data from the Medical Research Council's National Survey of Health and Development-the 1946 British birth cohort. Multi-channel sequence analysis was used to create a typology of eight work-family life course types combining information on work, partnerships and parenthood between ages 16-51. Linear regression tested associations between work-family types and metabolic outcomes at age 53 on multiply imputed data (20 imputations) of >2,400 participants. Compared with men with strong ties to employment and early transitions to family life, men who made later transitions to parenthood and maintained strong ties to paid work had smaller waist circumferences (-2.16cm, 95% CI: -3.73, -0.59), lower triglycerides (9.78% lower, 95% CI: 0.81, 17.94) and lower blood pressure (systolic: -4.03mmHg, 95% CI: -6.93, -1.13; diastolic: -2.34mmHg, 95% CI: -4.15, -0.53). Married men and women who didn't have children had increased high density lipoprotein cholesterol (7.23% higher, 95% CI: 0.68, 14.21) and lower waist circumferences (-4.67cm, 95% CI: -8.37, -0.97), respectively. For men later transitions to parenthood combined with strong ties to paid work were linked to reduced metabolic risk in mid-life. Fewer differences between work-family types and metabolic markers were seen for women.
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Affiliation(s)
- Rebecca E. Lacey
- Department of Epidemiology and Public Health, University College London, London, United Kingdom
| | - Meena Kumari
- Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom
| | - Amanda Sacker
- Department of Epidemiology and Public Health, University College London, London, United Kingdom
| | - Mai Stafford
- Medical Research Council Unit for Lifelong Health and Ageing, University College London, London, United Kingdom
| | - Diana Kuh
- Medical Research Council Unit for Lifelong Health and Ageing, University College London, London, United Kingdom
| | - Anne McMunn
- Department of Epidemiology and Public Health, University College London, London, United Kingdom
- * E-mail:
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d'Amore A, Caiola S, Maroccia E, Loizzo A. Postnatal Stress in Mice: Effects on Body Fat, Plasma Lipids, Glucose and Insulin. Nutr Neurosci 2016; 3:207-14. [PMID: 27414054 DOI: 10.1080/1028415x.2000.11747317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Mice pups were exposed to stressful stimuli everyday during the first 3 weeks of life. Body weight, food intake and spontaneous locomotor activity, triglycerides, cholesterol, phospholipids, glucose and insulin basal levels, as well as epididymal fat pad weight and its cell volume were measured in stressed and control animals. Results indicated that postnatal stressful manipulations induced an increase in body weight, epididymal fat pad weight and its cell volume, as well as in insulin, glucose, cholesterol and triglycerides plasma levels, at 4 months of age. No significant changes in food consumption, locomotor activity and phospholipids plasma levels were found. Present data suggest that early stressful manipulations may induce residual effects on lipid and glucid metabolism.
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Affiliation(s)
- A d'Amore
- a Laboratorio di Alimenti , Istituto Superiore di Sanità , Viale Regina Elena 299, 00161 Rome , Italy
| | - S Caiola
- b Laboratorio di Biochimica Clinica , Istituto Superiore di Sanità , Viale Regina Elena 299, 00161 Rome , Italy
| | - E Maroccia
- b Laboratorio di Biochimica Clinica , Istituto Superiore di Sanità , Viale Regina Elena 299, 00161 Rome , Italy
| | - A Loizzo
- c Laboratorio di Farmacologia , Istituto Superiore di Sanità , Viale Regina Elena 299, 00161 Rome , Italy
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Cabanac M, Michel C, Gosselin C. Corticotropin Releasing Hormone and Body Weight Regulation: The Behavioral Approach. Nutr Neurosci 2016; 2:385-401. [DOI: 10.1080/1028415x.1999.11747293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Mwanza C, Chen Z, Zhang Q, Chen S, Wang W, Deng H. Simultaneous HPLC-APCI-MS/MS quantification of endogenous cannabinoids and glucocorticoids in hair. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1028:1-10. [PMID: 27318292 DOI: 10.1016/j.jchromb.2016.06.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 05/30/2016] [Accepted: 06/01/2016] [Indexed: 01/08/2023]
Abstract
Hair matrix could retrospectively record association of endogenous cannabinoids (e.g. 2-arachidonoyl glycerol, 2-AG and N-arachidonoyl-ethanolamine, AEA) and glucocorticoids (e.g. cortisol and cortisone) in a myriad of physiological functions. However, depending on the extraction conditions, the spontaneous isomerization of 2-AG to 1-arachidonoylglycerol (1-AG) and the possible rearrangement of O-arachidonoyl ethanolamine (OAEA) to AEA in various sample matrices could be major obstacles encountered in the detection of both 2-AG and AEA. This study aimed to develop a novel method for simultaneous quantification of 2-AG, AEA, cortisol and cortisone in hair. Methanol was used as the incubation solution and an acidic mixture of deionized water and methanol were utilized as mobile phase in order to avert possible rearrangements of both OAEA and 2-AG. The analyses were performed on a high-performance liquid chromatography tandem mass spectrometer with atmosphere pressure chemical ionization in positive mode. The method showed good linearity in the range of 3.0-250pg/mg for AEA, 15.0-1250pg/mg for 2-AG and 1-250pg/mg for cortisol and cortisone. Limit of detection was 1.5pg/mg for AEA, 6.0pg/mg for 2-AG and 0.5pg/mg for cortisol and cortisone. For all four analytes, intra and inter-day coefficients of variation were less than 20% and recovery above 90%. Population analyses in 473 hair samples established that 2-AG was significantly correlated with AEA. 2-AG was significantly and positively correlated with cortisol and cortisone. There was a significant positive correlation of AEA with cortisol, but not with cortisone. Obese participants showed a significantly higher concentration of cortisone and 2-AG. Males showed significantly higher 2-AG and cortisone levels but significantly lower AEA levels than females.
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Affiliation(s)
- Christopher Mwanza
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, and Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China; Department of Chemistry, School of Natural Sciences, The University of Zambia, Lusaka 10100, Zambia
| | - Zheng Chen
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, and Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China
| | - Quan Zhang
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, and Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China
| | - Shenghuo Chen
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, and Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China
| | - Weiwen Wang
- Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Science, Beijing 100101, China
| | - Huihua Deng
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, and Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China; Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Science, Beijing 100101, China.
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Stress-induced alterations in estradiol sensitivity increase risk for obesity in women. Physiol Behav 2016; 166:56-64. [PMID: 27182047 DOI: 10.1016/j.physbeh.2016.05.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 04/04/2016] [Accepted: 05/11/2016] [Indexed: 02/02/2023]
Abstract
The prevalence of obesity in the United States continues to rise, increasing individual vulnerability to an array of adverse health outcomes. One factor that has been implicated causally in the increased accumulation of fat and excess food intake is the activity of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis in the face of relentless stressor exposure. However, translational and clinical research continues to understudy the effects sex and gonadal hormones and LHPA axis dysfunction in the etiology of obesity even though women continue to be at greater risk than men for stress-induced disorders, including depression, emotional feeding and obesity. The current review will emphasize the need for sex-specific evaluation of the relationship between stress exposure and LHPA axis activity on individual risk for obesity by summarizing data generated by animal models currently being leveraged to determine the etiology of stress-induced alterations in feeding behavior and metabolism. There exists a clear lack of translational models that have been used to study female-specific risk. One translational model of psychosocial stress exposure that has proven fruitful in elucidating potential mechanisms by which females are at increased risk for stress-induced adverse health outcomes is that of social subordination in socially housed female macaque monkeys. Data from subordinate female monkeys suggest that increased risk for emotional eating and the development of obesity in females may be due to LHPA axis-induced changes in the behavioral and physiological sensitivity of estradiol. The lack in understanding of the mechanisms underlying these alterations necessitate the need to account for the effects of sex and gonadal hormones in the rationale, design, implementation, analysis and interpretation of results in our studies of stress axis function in obesity. Doing so may lead to the identification of novel therapeutic targets with which to combat stress-induced obesity exclusively in females.
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Hart KA, Wochele DM, Norton NA, McFarlane D, Wooldridge AA, Frank N. Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses. J Vet Intern Med 2016; 30:653-63. [PMID: 26860336 PMCID: PMC4913614 DOI: 10.1111/jvim.13839] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/04/2015] [Accepted: 01/18/2016] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Increased free cortisol fraction is associated with insulin dysregulation (ID) in people with Metabolic Syndrome and Cushing's Disease. Free cortisol has not been investigated in equine endocrine disorders. HYPOTHESES (1) In healthy horses, sex, age, body condition score (BCS), and season impact free cortisol; (2) free cortisol is increased in horses with Pituitary Pars Intermedia Dysfunction (PPID) or Equine Metabolic Syndrome (EMS). ANIMALS Fifty-seven healthy horses; 40 horses and ponies with PPID (n = 20) or EMS (n = 20). METHODS Prospective study. Serum collected seasonally from healthy animals and archived serum from PPID and EMS animals was analyzed for insulin, total and free cortisol concentrations, and free cortisol fraction (FCF). Linear mixed models were used to determine effects of age, sex, season, and BCS on hormones in controls. Hormone measurements were compared between disease groups and age- and season-matched controls with t-tests. EMS and hyperinsulinemic PPID animals were combined in an ID (hyperinsulinemia) group. RESULTS Free cortisol concentrations were increased in overweight/obese controls (0.3 ± 0.1 μg/dL) compared to lean controls (0.2 ± 0.1 μg/dL; P = .017). Mean FCF was significantly higher in animals with PPID (8.8 ± 5.8 μg/dL, P = .005) or ID (8.8 ± 10.2 μg/dL, P = .039) than controls (5.0 ± 0.9 μg/dL), but total cortisol concentrations were similar (P ≥ .350) (PPID: 4.2 ± 4.3 μg/dL; ID: 5.0 ± 4.5 μg/dL; controls: 4.6 ± 1.7 and 5.1 ± 2.1 μg/dL). CONCLUSIONS AND CLINICAL IMPORTANCE Increased FCF is associated with obesity in healthy horses and with ID (hyperinsulinemia) in horses and ponies with endocrine disease. Decreased plasma cortisol-binding capacity could be a component of these endocrine disorders in horses.
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Affiliation(s)
- K A Hart
- University of Georgia College of Veterinary Medicine, Athens, GA
| | - D M Wochele
- University of Georgia College of Veterinary Medicine, Athens, GA
| | - N A Norton
- University of Georgia College of Veterinary Medicine, Athens, GA
| | - D McFarlane
- Oklahoma State College of Veterinary Medicine, Stillwater, OK
| | - A A Wooldridge
- Auburn University College of Veterinary Medicine, Auburn, AL
| | - N Frank
- Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA
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Schaalan M, Mohamed W, Rahmo R. Association of cardiac NT pro-β-type natriuretic peptide with metabolic and endothelial risk factors in young obese hypertensive patients: a perspective on the hypothalamic pituitary adrenal axis activation. Diabetol Metab Syndr 2016; 8:52. [PMID: 27478508 PMCID: PMC4966595 DOI: 10.1186/s13098-016-0164-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 07/10/2016] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND In practice, there is increasing recognition of the importance of hypothalamic pituitary adrenal axis in the cardiovascular disease progression. The association of brain natriuretic peptide with obesity and characteristics of the metabolic syndrome in adults and aged patients is well established, but that in pediatrics needs thorough elucidation. AIM The aim of this study was to assess the association of hypothalamic pituitary adrenal axis mediators (cortisol and aldosterone) with plasma NT-pro β-type natriuretic peptide (NT-proBNP) levels on metabolic, immune-inflammatory and endothelial markers in young obese pediatric patients. METHODS This is achieved by recruitment of 60 young (13-17 years) obese pediatric cohorts who are further subclassified according to their stage of hypertension; normotensive, prehypertensive and hypertensive patients. RESULTS The study showed significant differences in the metabolic parameters (glucose, insulin and HOMA-index) among the three obese young patient groups. Levels of cortisol and aldosterone, as well as NT-proBNP levels are positively associated with characteristics of the metabolic syndrome; blood pressure, BMI, HOMA index in all three obese groups. However, their association to the lipid profile was insignificant. These increases aligned harmonically with the assessed immune-inflammatory markers; CRP, TNF-α, and IL-23, as well as levels of sICAM, sVCAM and p-selectin, reflecting the involvement of mast cells and inflammatory effects on the vascular endothelium. ROC analysis revealed their beneficial addition as promising biomarkers for a better prognostic profile of hypertension-induced cardiovascular risk. CONCLUSION Early detection of NT-proBNP, cortisol and aldosterone levels in pre-hypertension stage added to the immune-inflammatory mediators may improve the coronary risk assessment in young Egyptian patients.
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Affiliation(s)
- Mona Schaalan
- Department of Biochemistry and Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Misr International University, Km 28, Cairo-Ismailia Road, Cairo, Heliopolis, PO Box 1, Cairo, Egypt
| | - Waleed Mohamed
- Chemistry Department, Cairo General Hospital, Cairo, Egypt
| | - Rania Rahmo
- Pharmacology and Toxicology Department, Misr International University, Cairo, Egypt
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Incollingo Rodriguez AC, Epel ES, White ML, Standen EC, Seckl JR, Tomiyama AJ. Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review. Psychoneuroendocrinology 2015; 62:301-18. [PMID: 26356039 DOI: 10.1016/j.psyneuen.2015.08.014] [Citation(s) in RCA: 274] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 08/18/2015] [Accepted: 08/18/2015] [Indexed: 12/29/2022]
Abstract
BACKGROUND Although there is substantial evidence of differential hypothalamic-pituitary-adrenal (HPA) axis activity in both generalized and abdominal obesity, consistent trends in obesity-related HPA axis perturbations have yet to be identified. OBJECTIVES To systematically review the existing literature on HPA activity in obesity, identify possible explanations for inconsistencies in the literature, and suggest methodological improvements for future study. DATA SOURCES Included papers used Pubmed, Google Scholar, and the University of California Library search engines with search terms body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, sagittal diameter, abdominal versus peripheral body fat distribution, body fat percentage, DEXA, abdominal obesity, and cortisol with terms awakening response, slope, total daily output, reactivity, feedback sensitivity, long-term output, and 11β-HSD expression. STUDY ELIGIBILITY CRITERIA Empirical research papers were eligible provided that they included at least one type of obesity (general or abdominal), measured at least one relevant cortisol parameter, and a priori tested for a relationship between obesity and cortisol. RESULTS A general pattern of findings emerged where greater abdominal fat is associated with greater responsivity of the HPA axis, reflected in morning awakening and acute stress reactivity, but some studies did show underresponsiveness. When examined in adipocytes, there is a clear upregulation of cortisol output (due to greater expression of 11β-HSD1), but in hepatic tissue this cortisol is downregulated. Overall obesity (BMI) appears to also be related to a hyperresponsive HPA axis in many but not all studies, such as when acute reactivity is examined. LIMITATIONS The reviewed literature contains numerous inconsistencies and contradictions in research methodologies, sample characteristics, and results, which partially precluded the development of clear and reliable patterns of dysregulation in each investigated cortisol parameter. CONCLUSIONS AND IMPLICATIONS The literature to date is inconclusive, which may well arise from differential effects of generalized obesity vs. abdominal obesity or from modulators such as sex, sex hormones, and chronic stress. While the relationship between obesity and adipocyte cortisol seems to be clear, further research is warranted to understand how adipocyte cortisol metabolism influences circulating cortisol levels and to establish consistent patterns of perturbations in adrenal cortisol activity in both generalized and abdominal obesity.
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Affiliation(s)
| | - Elissa S Epel
- University of California, San Francisco, CA 94118, USA
| | - Megan L White
- University of California, Los Angeles, CA 90095, USA
| | | | - Jonathan R Seckl
- University of Edinburgh, Edinburgh EH1 1HT, Scotland, United Kingdom
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Hébert JR, Braun KL, Kaholokula JK, Armstead CA, Burch JB, Thompson B. Considering the Role of Stress in Populations of High-Risk, Underserved Community Networks Program Centers. Prog Community Health Partnersh 2015. [PMID: 26213406 DOI: 10.1353/cpr.2015.0028] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cancer disparities are associated with a broad range of sociocultural determinants of health that operate in community contexts. High-risk populations may be more vulnerable to social and environmental factors that lead to chronic stress. Theoretical and empirical research indicates that exposure to contextual and sociocultural stress alters biological systems, thereby influencing cancer risk, progression, and, ultimately, mortality. OBJECTIVE We sought to describe contextual pathways through which stress likely increases cancer risk in high-risk, underserved populations. METHODS This review presents a description of the link between contextual stressors and disease risk disparities within underserved communities, with a focus on 1) stress as a proximal link between biological processes, such as cytokine responses, inflammation, and cancer and 2) stress as a distal link to cancer through biobehavioral risk factors such as poor diet, physical inactivity, circadian rhythm or sleep disruption, and substance abuse. These concepts are illustrated through application to populations served by three National Cancer Institute-funded Community Networks Program Centers (CNPCs): African Americans in the Deep South (the South Carolina Cancer Disparities Community Network [SCCDCN]), Native Hawaiians ('Imi Hale-Native Hawaiian Cancer Network), and Latinos in the Lower Yakima Valley of Washington State (The Center for Hispanic Health Promotion: Reducing Cancer Disparities). CONCLUSIONS Stress experienced by the underserved communities represented in the CNPCs is marked by social, biological, and behavioral pathways that increase cancer risk. A case is presented to increase research on sociocultural determinants of health, stress, and cancer risk among racial/ethnic minorities in underserved communities.
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