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Perego Junior JE, Tomazi Silva K, Balani Rando AL, Sousa Lima M, Garcia RF, Pedrosa MMD. Glucose metabolism in the perfused liver did not improve with resistance training in male Swiss mice under caloric restriction. Arch Physiol Biochem 2025; 131:306-315. [PMID: 39392336 DOI: 10.1080/13813455.2024.2413626] [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: 12/17/2023] [Revised: 07/30/2024] [Accepted: 09/09/2024] [Indexed: 10/12/2024]
Abstract
CONTEXT Energy homeostasis is a primary factor for the survival of mammals. Many tissues and organs, among which is the liver, keep this homeostasis in varied circumstances, including caloric restriction (CR) and physical activity. OBJECTIVE This study investigated glucose metabolism using the following groups of eight-week-old male Swiss mice: CS, sedentary and fed freely; RS, sedentary and RT, trained, both under 30% CR (n = 20-23 per group). RESULTS Organs and fat depots of groups RS and RT were similar to CS, although body weight was lower. CR did not impair training performance nor affected systemic or hepatic glucose metabolism. Training combined with CR (group RT) improved in vivo glucose tolerance and did not affect liver gluconeogenesis. CONCLUSIONS The mice tolerated the prolonged moderate CR without impairment of their well-being, glucose homeostasis, and resistance training performance. But the higher liver gluconeogenic efficiency previously demonstrated using this training protocol in mice was not evidenced under CR.
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Affiliation(s)
| | - Kauane Tomazi Silva
- Program of Graduate Studies in Physiological Sciences, State University of Maringá, Maringá, PR, Brazil
| | | | - Mateus Sousa Lima
- Department of Biology, State University of Maringá, Maringá, PR, Brazil
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2
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Li HY, Wang Y, Ran M, Gao F, Zhu BY, Xiao HY, Xu C. Tacrolimus induces insulin receptor substrate 1 hyperphosphorylation and inhibits mTORc1/S6K1 cascade in HL7702 cells. World J Diabetes 2025; 16:97910. [PMID: 39959267 PMCID: PMC11718479 DOI: 10.4239/wjd.v16.i2.97910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/28/2024] [Accepted: 11/13/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Tacrolimus (FK506) is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival. However, it is linked to hyperglycemia and insulin resistance, contributing to new-onset diabetes after transplantation and negatively affecting islet function. AIM To study the effects of tacrolimus on the insulin signaling pathway of hepatocytes. METHODS HL7702 cells were treated with different concentrations of tacrolimus (0.1 mg/L, 1 mg/L, 5 mg/L) for 24 hours. The proteins involved in insulin signaling were detected by Western blotting. RESULTS Compared with the control group, phosphorylation of insulin receptor substrate (IRS) 1 at Ser 307 and Ser 323 were increased significantly when the tacrolimus concentration reached 1 and 5 mg/L. Phosphorylation of IRS1 at Ser 1101 was also increased, although not significantly. However, phosphorylation of Ribosomal protein S6 kinase beta-1 at Thr 389 was decreased significantly. The levels of phosphorylated glycogen synthase kinase 3α Ser 21 and Ser 9 were increased. Surprisingly, phosphorylation of glycogen synthase at Ser 641 was increased. There was no significant change in the activity of glycogen phosphorylase. CONCLUSION Tacrolimus has no direct effect on hepatic glucose metabolism, but inhibits IRS1-mediated insulin signaling. This may be one of the underlying mechanisms by which tacrolimus induces insulin resistance.
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Affiliation(s)
- Hao-Yan Li
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Yi Wang
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Min Ran
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Fei Gao
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Bo-Yu Zhu
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Hai-Ying Xiao
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Chun Xu
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Anti-diabetic effect of hesperidin on palmitate (PA)-treated HepG2 cells and high fat diet-induced obese mice. Food Res Int 2022; 162:112059. [DOI: 10.1016/j.foodres.2022.112059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/17/2022] [Accepted: 10/14/2022] [Indexed: 11/19/2022]
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Dayarathne LA, Ranaweera SS, Natraj P, Rajan P, Lee YJ, Han CH. The effects of naringenin and naringin on the glucose uptake and AMPK phosphorylation in high glucose treated HepG2 cells. J Vet Sci 2021; 22:e92. [PMID: 34854271 PMCID: PMC8636664 DOI: 10.4142/jvs.2021.22.e92] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/27/2021] [Accepted: 10/05/2021] [Indexed: 11/29/2022] Open
Abstract
Background Naringin and its aglycone naringenin are citrus-derived flavonoids with several pharmacological effects. On the other hand, the mechanism for the anti-diabetic effects of naringenin and naringin are controversial and remain to be clarified further. Objective This study examined the relationship between glucose uptake and AMP-activated protein kinase (AMPK) phosphorylation by naringenin and naringin in high glucose-treated HepG2 cells. Methods Glucose uptake was measured using the 2-NBDG fluorescent D-glucose analog. The phosphorylation levels of AMPK and GSK3β (Glycogen synthase kinase 3 beta) were observed by Western blotting. Molecular docking analysis was performed to evaluate the binding affinity of naringenin and naringin to the γ-subunit of AMPK. Results The treatment with naringenin and naringin stimulated glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Both flavonoids increased glucose uptake by promoting the phosphorylation of AMPK at Thr172 and increased the phosphorylation of GSK3β. Molecular docking analysis showed that both naringenin and naringin bind to the γ-subunit of AMPK with high binding affinities. In particular, naringin showed higher binding affinity than the true modulator, AMP with all three CBS domains (CBS1, 3, and 4) in the γ-subunit of AMPK. Therefore, both naringenin and naringin could be positive modulators of AMPK activation, which enhance glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Conclusions The increased phosphorylation of AMPK at Thr172 by naringenin and naringin might enhance glucose uptake regardless of insulin stimulation in high glucose treated HepG2 cells.
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Affiliation(s)
| | | | - Premkumar Natraj
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Korea
| | - Priyanka Rajan
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Korea
| | - Young Jae Lee
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Korea
| | - Chang-Hoon Han
- College of Veterinary Medicine, Jeju National University, Jeju 63243, Korea.
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Wang Y, Liu Q, Kang SG, Huang K, Tong T. Dietary Bioactive Ingredients Modulating the cAMP Signaling in Diabetes Treatment. Nutrients 2021; 13:nu13093038. [PMID: 34578916 PMCID: PMC8467569 DOI: 10.3390/nu13093038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
As the prevalence of diabetes increases progressively, research to develop new therapeutic approaches and the search for more bioactive compounds are attracting more attention. Over the past decades, studies have suggested that cyclic adenosine monophosphate (cAMP), the important intracellular second messenger, is a key regulator of metabolism and glucose homeostasis in diverse physiopathological states in multiple organs including the pancreas, liver, gut, skeletal muscle, adipose tissues, brain, and kidney. The multiple characteristics of dietary compounds and their favorable influence on diabetes pathogenesis, as well as their intersections with the cAMP signaling pathway, indicate that these compounds have a beneficial effect on the regulation of glucose homeostasis. In this review, we outline the current understanding of the diverse functions of cAMP in different organs involved in glucose homeostasis and show that a diversity of bioactive ingredients from foods activate or inhibit cAMP signaling, resulting in the improvement of the diabetic pathophysiological process. It aims to highlight the diabetes-preventative or -therapeutic potential of dietary bioactive ingredients targeting cAMP signaling.
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Affiliation(s)
- Yanan Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China;
| | - Qing Liu
- Jilin Green Food Engineering Research Institute, Changchun 130022, China;
| | - Seong-Gook Kang
- Department of Food Engineering, Mokpo National University, Muangun 58554, Korea;
| | - Kunlun Huang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China;
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
- Correspondence: (K.H.); (T.T.)
| | - Tao Tong
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China;
- Correspondence: (K.H.); (T.T.)
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Agrawal R, Reno CM, Sharma S, Christensen C, Huang Y, Fisher SJ. Insulin action in the brain regulates both central and peripheral functions. Am J Physiol Endocrinol Metab 2021; 321:E156-E163. [PMID: 34056920 PMCID: PMC8321819 DOI: 10.1152/ajpendo.00642.2020] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.
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Affiliation(s)
- Rahul Agrawal
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Candace M Reno
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Sunny Sharma
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Camille Christensen
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Yiqing Huang
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Simon J Fisher
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah
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8
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Ladyman SR, Brooks VL. Central actions of insulin during pregnancy and lactation. J Neuroendocrinol 2021; 33:e12946. [PMID: 33710714 PMCID: PMC9198112 DOI: 10.1111/jne.12946] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/24/2021] [Accepted: 01/27/2021] [Indexed: 12/17/2022]
Abstract
Pregnancy and lactation are highly metabolically demanding states. Maternal glucose is a key fuel source for the growth and development of the fetus, as well as for the production of milk during lactation. Hence, the maternal body undergoes major adaptations in the systems regulating glucose homeostasis to cope with the increased demand for glucose. As part of these changes, insulin levels are elevated during pregnancy and lower in lactation. The increased insulin secretion during pregnancy plays a vital role in the periphery; however, the potential effects of increased insulin action in the brain have not been widely investigated. In this review, we consider the impact of pregnancy on brain access and brain levels of insulin. Moreover, we explore the hypothesis that pregnancy is associated with site-specific central insulin resistance that is adaptive, allowing for the increases in peripheral insulin secretion without the consequences of increased central and peripheral insulin functions, such as to stimulate glucose uptake into maternal tissues or to inhibit food intake. Conversely, the loss of central insulin actions may impair other functions, such as insulin control of the autonomic nervous system. The potential role of low insulin in facilitating adaptive responses to lactation, such as hyperphagia and suppression of reproductive function, are also discussed. We end the review with a list of key research questions requiring resolution.
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Affiliation(s)
- Sharon R Ladyman
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Virginia L Brooks
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, USA
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Khant Aung Z, Grattan DR, Ladyman SR. Pregnancy-induced adaptation of central sensitivity to leptin and insulin. Mol Cell Endocrinol 2020; 516:110933. [PMID: 32707081 DOI: 10.1016/j.mce.2020.110933] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 06/22/2020] [Accepted: 06/29/2020] [Indexed: 02/07/2023]
Abstract
Pregnancy is a time of increased food intake and fat deposition in the mother, and adaptations of glucose homeostasis to meet the energy demands of the growing fetus. As part of these adaptations, leptin and insulin concentrations increase in the maternal circulation during pregnancy. Central effects of leptin and insulin, however, are counterproductive to pregnancy, as increased action of these hormones in the brain lead to suppression of food intake. To prevent this, it is well documented that pregnancy induces a state of leptin- and insulin-insensitivity in the brain, particularly the hypothalamus, in a range of species. While the mechanisms underlying leptin- or insulin-insensitivity during pregnancy vary between species, there is evidence of reduced transport into the brain, impaired activation of intracellular signalling pathways, including reduced leptin receptor expression, and attenuated activation of downstream neuronal pathways, especially for leptin insensitivity. Pregnancy-induced changes in prolactin, growth hormone and leptin are discussed in terms of their role in mediating this reduced response to leptin and insulin.
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Affiliation(s)
- Z Khant Aung
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, 9016, New Zealand
| | - D R Grattan
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, 9016, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, 1010, New Zealand
| | - S R Ladyman
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, 9016, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, 1010, New Zealand.
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10
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da Silva Teixeira S, Harrison K, Uzodike M, Rajapakshe K, Coarfa C, He Y, Xu Y, Sisley S. Vitamin D actions in neurons require the PI3K pathway for both enhancing insulin signaling and rapid depolarizing effects. J Steroid Biochem Mol Biol 2020; 200:105690. [PMID: 32408067 PMCID: PMC7397709 DOI: 10.1016/j.jsbmb.2020.105690] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 03/23/2020] [Accepted: 04/29/2020] [Indexed: 12/15/2022]
Abstract
Despite correlations between low vitamin D levels and diabetes incidence/severity, supplementation with vitamin D has not been widely effective in improving glucose parameters. This may be due to a lack of knowledge regarding how low vitamin D levels physiologically affect glucose homeostasis. We have previously shown that the brain may be a critical area for vitamin d-mediated action on peripheral glucose levels. However, the mechanisms for how vitamin D acts in the brain are unknown. We utilized a multimodal approach to determine the mechanisms by which vitamin D may act in the brain. We first performed an unbiased search (RNA-sequencing) for pathways affected by vitamin D. Vitamin D (125-dihydroxyvitamin D3; 1,25D3) delivered directly into the third ventricle of obese animals differentially regulated multiple pathways, including the insulin signaling pathway. The insulin signaling pathway includes PI3K, which is important in the brain for glucose regulation. Since others have shown that vitamin D acts through the PI3K pathway in non-neuronal cells (muscle and bone), we hypothesized that vitamin D may act in neurons through a PI3K-dependent pathway. In a hypothalamic cell-culture model (GT1-7 cells), we demonstrate that 1,25D3 increased phosphorylation of Akt in the presence of insulin. However, this was blocked with pre-treatment of wortmannin, a PI3K inhibitor. 1,25D3 increased gene transcription of several genes within the PI3K pathway, including Irs2 and p85, without affecting expression of InsR or Akt. Since we had previously shown that 1,25D3 has significant effects on neuronal function, we also tested if the PI3K pathway could mediate rapid actions of vitamin D. We found that 1,25D3 increased the firing frequency of neurons through a PI3K-dependent mechanism. Collectively, these data support that vitamin D enhances insulin signaling and neuronal excitability through PI3K dependent processes which involve both transcriptional and membrane-initiated signaling events.
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Affiliation(s)
- Silvania da Silva Teixeira
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, United States
| | - Keisha Harrison
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, United States
| | | | - Kimal Rajapakshe
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, United States
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, United States; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030, United States
| | - Yanlin He
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, United States
| | - Yong Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, United States
| | - Stephanie Sisley
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, United States.
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Grattan DR, Ladyman SR. Neurophysiological and cognitive changes in pregnancy. HANDBOOK OF CLINICAL NEUROLOGY 2020; 171:25-55. [PMID: 32736755 DOI: 10.1016/b978-0-444-64239-4.00002-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The hormonal fluctuations in pregnancy drive a wide range of adaptive changes in the maternal brain. These range from specific neurophysiological changes in the patterns of activity of individual neuronal populations, through to complete modification of circuit characteristics leading to fundamental changes in behavior. From a neurologic perspective, the key hormone changes are those of the sex steroids, estradiol and progesterone, secreted first from the ovary and then from the placenta, the adrenal glucocorticoid cortisol, as well as the anterior pituitary peptide hormone prolactin and its pregnancy-specific homolog placental lactogen. All of these hormones are markedly elevated during pregnancy and cross the blood-brain barrier to exert actions on neuronal populations through receptors expressed in specific regions. Many of the hormone-induced changes are in autonomic or homeostatic systems. For example, patterns of oxytocin and prolactin secretion are dramatically altered to support novel physiological functions. Appetite is increased and feedback responses to metabolic hormones such as leptin and insulin are suppressed to promote a positive energy balance. Fundamental physiological systems such as glucose homeostasis and thermoregulation are modified to optimize conditions for fetal development. In addition to these largely autonomic changes, there are also changes in mood, behavior, and higher processes such as cognition. This chapter summarizes the hormonal changes associated with pregnancy and reviews how these changes impact on brain function, drawing on examples from animal research, as well as available information about human pregnancy.
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Affiliation(s)
- David R Grattan
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
| | - Sharon R Ladyman
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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Kanai S, Shimada T, Narita T, Okabayashi K. Phosphofructokinase-1 and fructose bisphosphatase-1 in canine liver and kidney. J Vet Med Sci 2019; 81:1515-1521. [PMID: 31474665 PMCID: PMC6863710 DOI: 10.1292/jvms.19-0361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In healthy individuals, plasma glucose levels are maintained within a normal range.
During fasting, endogenous glucose is released either through glycogenolysis or
gluconeogenesis. Gluconeogenesis involves the formation of glucose-6-phosphate from a
variety of precursors followed by its subsequent hydrolysis to glucose. Gluconeogenesis
occurs in the liver and the kidney. In order to compare gluconeogenesis in canine liver
and kidney, the activity and expression of the rate limiting enzymes that catalyze the
fructose-6-phosphate and fructose 1,6-bisphosphate steps, namely, phosphofructokinase-1
(PFK-1) (glycolysis) and fructose bisphosphatase-1 (FBP-1) (gluconeogenesis), were
examined. Healthy male and female beagle dogs aged 1–2 years were euthanized humanely, and
samples of their liver and kidney were obtained for analysis. The levels of PFK-1 and
FBP-1 in canine liver and kidney were assessed by enzymatic assays, Western blotting, and
RT-qPCR. Enzyme assays showed that, in dogs, the kidney had higher specific activity of
PFK-1 and FBP-1 than the liver. Western blotting and RT-qPCR data demonstrated that of the
three different subunits (PFK-M, PFK-L, and PFK-P) the PFK-1 in canine liver mainly
comprised PFK-L, whereas the PFK-1 in the canine kidney comprised all three subunits. As a
result of these differences in the subunit composition of PFK-1, glucose metabolism might
be regulated differently in the liver and kidney.
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Affiliation(s)
- Shuichiro Kanai
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan.,Mutsuai Animal Hospital, 577-7 Kameino, Fujisawa, Kanagawa 252-0813, Japan
| | - Takuro Shimada
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Takanori Narita
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Ken Okabayashi
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
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Neuronal cAMP/PKA Signaling and Energy Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1090:31-48. [PMID: 30390284 DOI: 10.1007/978-981-13-1286-1_3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The brain plays a key role in the regulation of body weight and glucose metabolism. Peripheral signals including hormones, metabolites, and neural afferent signals are received and processed by the brain which in turn elicits proper behavioral and metabolic responses for maintaining energy and glucose homeostasis. The cAMP/protein kinase A (PKA) pathway acts downstream G-protein-coupled receptors (GPCR) to mediate the physiological effects of many hormones and neurotransmitters. Activated PKA phosphorylates various proteins including ion channels, enzymes, and transcription factors and regulates their activity. Recent studies have shown that neuronal cAMP/PKA activity in multiple brain regions are involved in the regulation of feeding, energy expenditure, and glucose homeostasis. In this chapter I summarize recent genetic and pharmacological studies concerning the regulation of body weight and glucose homeostasis by cAMP/PKA signaling in the brain.
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Baicalein improves glucose metabolism in insulin resistant HepG2 cells. Eur J Pharmacol 2019; 854:187-193. [PMID: 30970232 DOI: 10.1016/j.ejphar.2019.04.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/30/2019] [Accepted: 04/02/2019] [Indexed: 01/06/2023]
Abstract
Insulin resistance (IR) is the primary pathogenesis of Type 2 diabetes mellitus (T2DM). Scutellaria baicalensis Georgi is a traditional Chinese herbal medicine, often used in the clinical treatment of T2DM. Baicalein which is considered to have anti-IR effects is one of its active ingredients. IR-induced HepG2 cells were used to investigate the effect of baicalein on glucose metabolism and insulin-signaling pathway, using metformin as a positive control. We found that the use of both baicalein and metformin increased the glucose consumption of IR cells, as well as increasing the pyruvate kinase (PK) and glucokinase (GCK) activity. Also increased was the expression levels of insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) pathway and glucose transporter 2 (GLUT2). Reduced expression levels were found in that of glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA. The results confirmed that baicalein (10-6 and 10-5 mol/L) promotes glucose uptake and glycolysis, inhibits gluconeogenesis of hepatocytes to improve glucose metabolism, and may be as a result from regulation of InsR/IRS-1/PI3K/AKT pathway. Additionally, baicalein has large concentration range on inhibiting IR, and at lower concentrations has strong anti-IR hepatocyte activity.
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Guilherme A, Henriques F, Bedard AH, Czech MP. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nat Rev Endocrinol 2019; 15:207-225. [PMID: 30733616 PMCID: PMC7073451 DOI: 10.1038/s41574-019-0165-y] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Adipose tissue comprises adipocytes and many other cell types that engage in dynamic crosstalk in a highly innervated and vascularized tissue matrix. Although adipose tissue has been studied for decades, it has been appreciated only in the past 5 years that extensive arborization of nerve fibres has a dominant role in regulating the function of adipose tissue. This Review summarizes the latest literature, which suggests that adipocytes signal to local sensory nerve fibres in response to perturbations in lipolysis and lipogenesis. Such adipocyte signalling to the central nervous system causes sympathetic output to distant adipose depots and potentially other metabolic tissues to regulate systemic glucose homeostasis. Paracrine factors identified in the past few years that mediate such adipocyte-neuron crosstalk are also reviewed. Similarly, immune cells and endothelial cells within adipose tissue communicate with local nerve fibres to modulate neurotransmitter tone, blood flow, adipocyte differentiation and energy expenditure, including adipose browning to produce heat. This understudied field of neurometabolism related to adipose tissue biology has great potential to reveal new mechanistic insights and potential therapeutic strategies for obesity and type 2 diabetes mellitus.
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Affiliation(s)
- Adilson Guilherme
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Felipe Henriques
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Alexander H Bedard
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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Scarlett JM, Muta K, Brown JM, Rojas JM, Matsen ME, Acharya NK, Secher A, Ingvorsen C, Jorgensen R, Høeg-Jensen T, Stefanovski D, Bergman RN, Piccinini F, Kaiyala KJ, Shiota M, Morton GJ, Schwartz MW. Peripheral Mechanisms Mediating the Sustained Antidiabetic Action of FGF1 in the Brain. Diabetes 2019; 68:654-664. [PMID: 30523024 PMCID: PMC6385755 DOI: 10.2337/db18-0498] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 10/29/2018] [Indexed: 12/24/2022]
Abstract
We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic β-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of β-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of β-cell function and stimulation of HGU through increased hepatic glucokinase activity.
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Affiliation(s)
- Jarrad M Scarlett
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
- Gastroenterology and Hepatology, Department of Pediatrics, University of Washington, Seattle, WA
| | - Kenjiro Muta
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
| | - Jenny M Brown
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
| | - Jennifer M Rojas
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
- Department of Physiology, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Miles E Matsen
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
| | - Nikhil K Acharya
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
| | | | | | | | | | - Darko Stefanovski
- New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
| | - Richard N Bergman
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Francesca Piccinini
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Karl J Kaiyala
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA
| | - Masakazu Shiota
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Gregory J Morton
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
| | - Michael W Schwartz
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA
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17
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Palacios OM, Kramer M, Maki KC. Diet and prevention of type 2 diabetes mellitus: beyond weight loss and exercise. Expert Rev Endocrinol Metab 2019; 14:1-12. [PMID: 30521416 DOI: 10.1080/17446651.2019.1554430] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 11/28/2018] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Insulin resistance (IR) and pancreatic beta-cell dysfunction are core pathophysiologic features of type 2 diabetes mellitus (T2DM). Select lifestyle and pharmacologic interventions, including weight loss, physical activity, a Mediterranean diet intervention, and hypoglycemic agents, have been shown to prevent or delay T2DM. However, dietary factors other than weight loss may also impact risk, mainly through effects to enhance insulin sensitivity, although some may also directly or indirectly impact pancreatic beta-cell function. AREAS COVERED A literature review of observational studies and randomized controlled trials (RCTs) was conducted, and the research indicates dietary factors showing promise for reducing T2DM risk include higher intakes of cereal fibers, unsaturated fatty acids, magnesium, and polyphenols (e.g. anthocyanins), while reducing dietary glycemic load, added sugars, and high-sugar beverages. EXPERT COMMENTARY While these dietary factors are mainly supported by evidence from observational studies and RCTs of surrogate markers for T2DM, they are consistent with current recommendations to emphasize consumption of whole grains, nuts, seeds, legumes, seafood, fruits, and vegetables, while limiting intakes of saturated fatty acids, refined carbohydrates, and processed meats. Additional dietary intervention RCTs are needed to assess the efficacy of these promising dietary interventions for delaying or preventing the onset of T2DM.
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Affiliation(s)
- Orsolya M Palacios
- a Midwest Biomedical Research/Center for Metabolic and Cardiovascular Health , Glen Ellyn , IL , USA
| | | | - Kevin C Maki
- a Midwest Biomedical Research/Center for Metabolic and Cardiovascular Health , Glen Ellyn , IL , USA
- b MB Clinical Research , Boca Raton , FL , USA
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Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats. Int J Mol Sci 2018; 19:ijms19113539. [PMID: 30424007 PMCID: PMC6274985 DOI: 10.3390/ijms19113539] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/22/2018] [Accepted: 11/06/2018] [Indexed: 12/23/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats.
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Otowa-Suematsu N, Sakaguchi K, Nakamura T, Hara K, Kishi M, Hashimoto N, Yokota K, Yoshino H, Kuroki Y, Nishiumi T, Sou A, Komada H, Okada Y, Hirota Y, Tamori Y, Ogawa W. Comprehensive Evaluation of Combination Therapy with Basal Insulin and Either Lixisenatide or Vildagliptin in Japanese Patients with Type 2 Diabetes: A Randomized, Open-Label, Parallel-Group, Multicenter Study. Diabetes Ther 2018; 9:2067-2079. [PMID: 30206903 PMCID: PMC6167300 DOI: 10.1007/s13300-018-0505-2] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Indexed: 11/28/2022] Open
Abstract
INTRODUCTION We comprehensively evaluated the effects of combination therapy with insulin glargine and the incretin-based drugs lixisenatide or vildagliptin in Japanese patients with type 2 diabetes. METHODS In this 12-week, randomized, open-label, parallel-group, multicenter study (GLP-ONE Kobe), the incretin-based drug sitagliptin was randomly switched to lixisenatide (20 μg/day, n = 18) or vildagliptin (100 mg/day, n = 20) in patients with inadequate glycemic control despite combination therapy with insulin glargine and sitagliptin. The dose of insulin glargine was titrated after the switch to maintain fasting blood glucose at approximately 110 mg/dL. The primary end points of the study were the change in glycosylated hemoglobin (HbA1c) level between before and 12 weeks after the treatment switch, the proportion of patients achieving an HbA1c level below 7.0%, and the postprandial increase in glucose concentration as assessed by self-monitoring of blood glucose. RESULTS The change in HbA1c level from baseline to 12 weeks did not differ significantly between the lixisenatide and vildagliptin groups (- 0.6 ± 0.7% and - 0.6 ± 1.2%, respectively, P = 0.920). Neither the proportion of patients achieving an HbA1c level below 7.0% nor the postprandial increase in glucose concentration was different between two groups. Body weight and serum low density lipoprotein (LDL) cholesterol level decreased significantly in the lixisenatide and vildagliptin groups, respectively. Both drugs were associated with mild gastrointestinal symptoms but not with severe hypoglycemia. Vildagliptin was associated with elevation of serum aspartate transaminase. Treatment satisfaction as assessed with the Diabetes Treatment Satisfaction Questionnaire did not differ significantly between the two groups. CONCLUSION The combinations of basal insulin and either lixisenatide or vildagliptin have similar efficacies with regard to improvement of glycemic control. TRIAL REGISTRATION This trial has been registered with UMIN (No. 000010769).
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Affiliation(s)
- Natsu Otowa-Suematsu
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazuhiko Sakaguchi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
- Division of General Internal Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Tomoaki Nakamura
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kenta Hara
- Department of Diabetes and Endocrine disease, Kita-harima Medical Center, Ono, Japan
| | - Minoru Kishi
- Department of Internal Medicine, Nishiwaki Municipal Hospital, Nishiwaki, Japan
| | - Naoko Hashimoto
- Department of Diabetes and Endocrinology, Hyogo Brain and Heart Center, Himeji, Japan
| | - Kazuki Yokota
- Department of Internal Medicine, Jinkeikai Ishii Hospital, Akashi, Japan
| | - Hiroshi Yoshino
- Department of Internal Medicine, Shinsuma General Hospital, Kobe, Japan
| | - Yasuo Kuroki
- Department of Internal Medicine, Kobe Century Memorial Hospital, Kobe, Japan
| | - Tomoko Nishiumi
- Department of Diabetes and Endocrinology, Kobe Rosai Hospital, Kobe, Japan
| | - Anna Sou
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hisako Komada
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuko Okada
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yushi Hirota
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshikazu Tamori
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Creative Health Promotion, Department of Social/Community Medicine and Health Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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20
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Zhang Y, Thai K, Jin T, Woo M, Gilbert RE. SIRT1 activation attenuates α cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice. Sci Rep 2018; 8:13972. [PMID: 30228292 PMCID: PMC6143559 DOI: 10.1038/s41598-018-32351-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 09/04/2018] [Indexed: 12/19/2022] Open
Abstract
The NAD+-dependent lysine deacetylase, Sirtuin 1 (SIRT1), plays a central role in metabolic regulation. With type 1 diabetes a disease that is characterised by metabolic dysregulation, we sought to assess the impact of SIRT1 activation in experimental, streptozotocin (STZ)-induced diabetes. CD1 mice with and without STZ-induced diabetes were randomized to receive the SIRT1 activating compound, SRT3025, or vehicle over 20 weeks. Vehicle treated STZ-CD1 mice developed severe hyperglycaemia with near-absent circulating insulin and widespread beta cell loss in association with hyperglucagonaemia and expanded islet alpha cell mass. Without affecting ß-cell mass or circulating insulin, diabetic mice that received SRT3025 had substantially improved glycaemic control with greatly reduced islet α cell mass and lower plasma glucagon concentrations. Consistent with reduced glucagon abundance, the diabetes-associated overexpression of key gluconeogenic enzymes, glucose-6-phosphatase and PEPCK were also lowered by SRT3025. Incubating cultured α cells with SRT3025 diminished their glucagon secretion and proliferative activity in association with a reduction in the α cell associated transcription factor, Aristaless Related Homeobox (Arx). By reducing the paradoxical increase in glucagon, SIRT1 activation may offer a new, α-cell centric approach to the treatment of type 1 diabetes.
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Affiliation(s)
- Yanling Zhang
- St. Michael's Hospital, Keenan Research Centre, Li Ka Shing Knowledge Institute, Toronto, M5B 1W8, Canada
| | - Kerri Thai
- St. Michael's Hospital, Keenan Research Centre, Li Ka Shing Knowledge Institute, Toronto, M5B 1W8, Canada
| | - Tianru Jin
- Toronto General Hospital Research Institute (TGHRI), Toronto, ON, M5G 2C4, Canada
| | - Minna Woo
- Toronto General Hospital Research Institute (TGHRI), Toronto, ON, M5G 2C4, Canada
| | - Richard E Gilbert
- St. Michael's Hospital, Keenan Research Centre, Li Ka Shing Knowledge Institute, Toronto, M5B 1W8, Canada.
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21
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Pozo M, Claret M. Hypothalamic Control of Systemic Glucose Homeostasis: The Pancreas Connection. Trends Endocrinol Metab 2018; 29:581-594. [PMID: 29866501 DOI: 10.1016/j.tem.2018.05.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/10/2018] [Accepted: 05/12/2018] [Indexed: 12/22/2022]
Abstract
Maintenance of glucose homeostasis is mandatory for organismal survival. It is accomplished by complex and coordinated interplay between glucose detection mechanisms and multiple effector systems. The brain, in particular homeostatic regions such as the hypothalamus, plays a crucial role in orchestrating such a highly integral response. We review here current understanding of how the hypothalamus senses glucose availability and participates in systemic glucose homeostasis. We provide an update of the relevant signaling pathways and neuronal subsets involved, as well as of the mechanisms modulating metabolic processes in peripheral tissues such as liver, skeletal muscle, fat, and especially the pancreas. We also discuss the relevance of these networks in human biology and prevalent metabolic conditions such as diabetes and obesity.
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Affiliation(s)
- Macarena Pozo
- Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Marc Claret
- Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
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22
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Harrison K, Sisley S. Vitamin D and the paraventricular nucleus: Relevance for type 2 diabetes. J Steroid Biochem Mol Biol 2018; 177:125-128. [PMID: 28993246 DOI: 10.1016/j.jsbmb.2017.10.005] [Citation(s) in RCA: 2] [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: 05/06/2017] [Revised: 10/02/2017] [Accepted: 10/05/2017] [Indexed: 12/22/2022]
Abstract
Vitamin D deficiency is linked to type 2 diabetes and we recently showed this may be through action of vitamin D in the paraventricular nuclei (PVN) in the hypothalamus of the brain. This review focuses on the known roles of the PVN in glucose control and how previously discovered actions of vitamin D in other tissues may translate to action in the PVN. Specifically, we focus on the role of insulin and inflammation in the hypothalamus and how these may be modified through vitamin D action.
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Affiliation(s)
- Keisha Harrison
- Department of Pediatrics, Baylor College of Medicine, 1100 Bates Avenue, Houston, TX 77030, USA.
| | - Stephanie Sisley
- Department of Pediatrics, Baylor College of Medicine, 1100 Bates Avenue, Houston, TX 77030, USA.
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23
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Sabatini PV, Speckmann T, Nian C, Glavas MM, Wong CK, Yoon JS, Kin T, Shapiro AMJ, Gibson WT, Verchere CB, Lynn FC. Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells. Cell Rep 2018; 22:163-174. [PMID: 29298418 DOI: 10.1016/j.celrep.2017.12.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 10/27/2017] [Accepted: 12/08/2017] [Indexed: 02/07/2023] Open
Abstract
Depolarization of neuroendocrine cells results in calcium influx, which induces vesicle exocytosis and alters gene expression. These processes, along with the restoration of resting membrane potential, are energy intensive. We hypothesized that cellular mechanisms exist to maximize energy production during excitation. Here, we demonstrate that NPAS4, an immediate early basic helix-loop-helix (bHLH)-PAS transcription factor, acts to maximize energy production by suppressing hypoxia-inducible factor 1α (HIF1α). As such, knockout of Npas4 from insulin-producing β cells results in reduced OXPHOS, loss of insulin secretion, β cell dedifferentiation, and type 2 diabetes. NPAS4 plays a similar role in the nutrient-sensing cells of the hypothalamus. Its knockout here results in increased food intake, reduced locomotor activity, and elevated peripheral glucose production. In conclusion, NPAS4 is critical for the coordination of metabolism during the stimulation of electrically excitable cells; its loss leads to the defects in cellular metabolism that underlie the cellular dysfunction that occurs in metabolic disease.
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Affiliation(s)
- Paul V Sabatini
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Thilo Speckmann
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Cuilan Nian
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Maria M Glavas
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Chi Kin Wong
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Ji Soo Yoon
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Tatsuya Kin
- Department of Surgery and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - A M James Shapiro
- Department of Surgery and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - William T Gibson
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - C Bruce Verchere
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Francis C Lynn
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
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24
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Ladyman SR, Grattan DR. Region-Specific Suppression of Hypothalamic Responses to Insulin To Adapt to Elevated Maternal Insulin Secretion During Pregnancy. Endocrinology 2017; 158:4257-4269. [PMID: 29029017 DOI: 10.1210/en.2017-00600] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/22/2017] [Indexed: 01/22/2023]
Abstract
As part of the adaptation of maternal glucose regulation during pregnancy to ensure glucose provision to the fetus, maternal insulin concentrations become elevated. However, increased central actions of insulin, such as suppression of appetite, would be maladaptive during pregnancy. We hypothesized that central nervous system targets of insulin become less responsive during pregnancy to prevent overstimulation by the increased circulating insulin concentrations. To test this hypothesis, we have measured insulin-induced phosphorylation of Akt (pAkt) in specific hypothalamic nuclei as an index of hypothalamic insulin responsiveness. Despite higher endogenous insulin concentrations following feeding, arcuate nucleus pAkt levels were significantly lower in the pregnant group compared with the nonpregnant group. In response to an intracerebroventricular injection of insulin, insulin-induced pAkt was significantly reduced in the arcuate nucleus and ventromedial nucleus of pregnant rats compared with nonpregnant rats. Similar levels of insulin receptor β and PTEN, a negative regulator of the phosphoinositide 3-kinase/Akt pathway, were detected in hypothalamic areas of nonpregnant and pregnant rats. In the ventromedial nucleus, however, levels of phosphorylated PTEN were significantly lower in pregnancy, suggesting that reduced inactivation of PTEN may contribute to the attenuated insulin signaling in this area during pregnancy. In conclusion, these results demonstrate region-specific changes in responsiveness to insulin in the hypothalamus during pregnancy that may represent an adaptive response to minimize the impact of elevated circulating insulin on the maternal brain.
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Affiliation(s)
- Sharon R Ladyman
- Centre for Neuroendocrinology, University of Otago, New Zealand
- Department of Anatomy, University of Otago, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, New Zealand
| | - David R Grattan
- Centre for Neuroendocrinology, University of Otago, New Zealand
- Department of Anatomy, University of Otago, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, New Zealand
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Fernández Real JM, Moreno-Navarrete JM, Manco M. Iron influences on the Gut-Brain axis and development of type 2 diabetes. Crit Rev Food Sci Nutr 2017; 59:443-449. [DOI: 10.1080/10408398.2017.1376616] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- José Manuel Fernández Real
- University Hospital of Girona ‘Dr JosepTrueta’, Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona IdibGi
- CIBER Fisiopatología de la Obesidad y Nutrición, Girona, Spain
| | - José Maria Moreno-Navarrete
- University Hospital of Girona ‘Dr JosepTrueta’, Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona IdibGi
- CIBER Fisiopatología de la Obesidad y Nutrición, Girona, Spain
| | - Melania Manco
- Research Area for multifactorial diseases, Bambino Gesù Children's Hospital and Research Institute, Research Unit for Multifactorial Disease, Rome, Italy
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27
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Burke LK, Ogunnowo-Bada E, Georgescu T, Cristiano C, de Morentin PBM, Valencia Torres L, D'Agostino G, Riches C, Heeley N, Ruan Y, Rubinstein M, Low MJ, Myers MG, Rochford JJ, Evans ML, Heisler LK. Lorcaserin improves glycemic control via a melanocortin neurocircuit. Mol Metab 2017; 6:1092-1102. [PMID: 29031711 PMCID: PMC5641625 DOI: 10.1016/j.molmet.2017.07.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 07/05/2017] [Accepted: 07/10/2017] [Indexed: 02/07/2023] Open
Abstract
Objective The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Methods Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.
Obesity medication lorcaserin directly improves glycemic control without altering energy balance or body weight. Unlike current frontline type 2 diabetes medications, lorcaserin acts within the brain to improve glycemic control. Brain Pro-opiomelanocortin (POMC) peptides are a neurochemical mediator of lorcaserin's glucoregulatory effects. Lorcaserin increases insulin sensitivity, reduces hepatic glucose production and increases glucose disposal.
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Affiliation(s)
- Luke K Burke
- Department of Pharmacology, University of Cambridge, Cambridge, UK; Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Emmanuel Ogunnowo-Bada
- Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | | | | | | | - Lourdes Valencia Torres
- Department of Pharmacology, University of Cambridge, Cambridge, UK; The Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - Giuseppe D'Agostino
- Department of Pharmacology, University of Cambridge, Cambridge, UK; The Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - Christine Riches
- Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Nicholas Heeley
- Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Yue Ruan
- Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Marcelo Rubinstein
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina
| | - Malcolm J Low
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Martin G Myers
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | - Mark L Evans
- Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
| | - Lora K Heisler
- Department of Pharmacology, University of Cambridge, Cambridge, UK; The Rowett Institute, University of Aberdeen, Aberdeen, UK.
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Bergman RN, Iyer MS. Indirect Regulation of Endogenous Glucose Production by Insulin: The Single Gateway Hypothesis Revisited. Diabetes 2017. [PMID: 28637826 DOI: 10.2337/db16-1320] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
On the basis of studies that investigated the intraportal versus systemic insulin infusion and transendothelial transport of insulin, we proposed the "single gateway hypothesis," which supposes an indirect regulation of hepatic glucose production by insulin; the rate-limiting transport of insulin across the adipose tissue capillaries is responsible for the slow suppression of free fatty acids (FFAs), which in turn is responsible for delayed suppression of hepatic endogenous glucose production (EGP) during insulin infusion. Preventing the fall in plasma FFAs during insulin infusion either by administering intralipids or by inhibiting adipose tissue lipolysis led to failure in EGP suppression, thus supporting our hypothesis. More recently, mice lacking hepatic Foxo1 in addition to Akt1 and Akt2 (L-AktFoxo1TKO), all required for insulin signaling, surprisingly showed normal glycemia. Inhibiting the fall of plasma FFAs in these mice prevented the suppression of EGP during a clamp, reaffirming that the site of insulin action to control EGP is extrahepatic. Measuring whole-body turnover rates of glucose and FFAs in L-AktFoxo1TKO mice also confirmed that hepatic EGP was regulated by insulin-mediated control of FFAs. The knockout mouse model in combination with sophisticated molecular techniques confirmed our physiological findings and the single gateway hypothesis.
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Affiliation(s)
- Richard N Bergman
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, CA
| | - Malini S Iyer
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, CA
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29
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Cady G, Landeryou T, Garratt M, Kopchick JJ, Qi N, Garcia-Galiano D, Elias CF, Myers MG, Miller RA, Sandoval DA, Sadagurski M. Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons. Mol Metab 2017; 6:393-405. [PMID: 28462074 PMCID: PMC5404104 DOI: 10.1016/j.molmet.2017.03.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 02/28/2017] [Accepted: 03/04/2017] [Indexed: 12/22/2022] Open
Abstract
Objective The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. Methods To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (LeprEYFPΔGHR). The mice were generated by crossing the Leprcre on the cre-inducible ROSA26-EYFP mice to GHRL/L mice. Parameters of body composition and glucose homeostasis were evaluated. Results Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in LeprEYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in LeprEYFPΔGHR mice. Conclusion These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding.
GHR and LepRb are co-localized in the ARH, DMH and LHA neurons. GHR signaling does not regulate food intake and body weight in LepRb neurons. Diminished GHR signaling in LepRb neurons impairs hepatic glucose production.
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Key Words
- ARH, arcuate nucleus of the hypothalamus
- CNS, central nervous system
- DMH, dorsomedial hypothalamic nucleus
- GH, growth hormone
- GHR, growth hormone receptor
- Glucose production
- Growth hormone receptor
- Hypothalamus
- LHA, lateral hypothalamus
- Lepr, leptin receptor
- Leptin receptor
- Liver
- POMC, proopiomelanocortin
- PVH, paraventricular hypothalamic nucleus
- Stat3, signal transducer and activator of transcription 3
- Stat5, signal transducer and activator of transcription 5
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Affiliation(s)
- Gillian Cady
- Department of Pathology and Geriatrics Center, University of Michigan Medical School, USA
| | - Taylor Landeryou
- Department of Pathology and Geriatrics Center, University of Michigan Medical School, USA
| | - Michael Garratt
- Department of Pathology and Geriatrics Center, University of Michigan Medical School, USA
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Nathan Qi
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - David Garcia-Galiano
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Carol F Elias
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Martin G Myers
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Richard A Miller
- Department of Pathology and Geriatrics Center, University of Michigan Medical School, USA
| | - Darleen A Sandoval
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Marianna Sadagurski
- Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
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30
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Iyer MS, Bergman RN, Korman JE, Woolcott OO, Kabir M, Victor RG, Clegg DJ, Kolka C. Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet. Diabetes 2016; 65:3453-3463. [PMID: 27495220 PMCID: PMC5079632 DOI: 10.2337/db16-0698] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 07/26/2016] [Indexed: 12/18/2022]
Abstract
Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. Thus, we hypothesized that inhibiting the SNS by using renal denervation (RDN) will improve insulin sensitivity (SI) in a nonhypertensive obese canine model. SI was measured using euglycemic-hyperinsulinemic clamp (EGC), before (week 0 [w0]) and after 6 weeks of high-fat diet (w6-HFD) feeding and after either RDN (HFD + RDN) or sham surgery (HFD + sham). As expected, HFD induced insulin resistance in the liver (sham 2.5 ± 0.6 vs. 0.7 ± 0.6 × 10-4 dL ⋅ kg-1 ⋅ min-1 ⋅ pmol/L-1 at w0 vs. w6-HFD [P < 0.05], respectively; HFD + RDN 1.6 ± 0.3 vs. 0.5 ± 0.3 × 10-4 dL ⋅ kg-1 ⋅ min-1 ⋅ pmol/L-1 at w0 vs. w6-HFD [P < 0.001], respectively). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic SI in HFD-fed animals (1.8 ± 0.3 × 10-4 dL ⋅ kg-1 ⋅ min-1 ⋅ pmol/L-1 at HFD + RDN [P < 0.001] vs. w6-HFD, [P not significant] vs. w0) by reducing hepatic gluconeogenic genes, including G6Pase, PEPCK, and FOXO1. The data suggest that RDN downregulated hepatic gluconeogenesis primarily by upregulating liver X receptor α through the natriuretic peptide pathway. In conclusion, bilateral RDN completely normalizes hepatic SI in obese canines. These preclinical data implicate a novel mechanistic role for the renal nerves in the regulation of insulin action specifically at the level of the liver and show that the renal nerves constitute a new therapeutic target to counteract insulin resistance.
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Affiliation(s)
- Malini S Iyer
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Richard N Bergman
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Jeremy E Korman
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Orison O Woolcott
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Morvarid Kabir
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Ronald G Victor
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
- Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Deborah J Clegg
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Cathryn Kolka
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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31
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Quaresma PGF, Weissmann L, Zanotto TM, Santos AC, de Matos AHB, Furigo IC, Simabuco FM, Donato J, Bittencourt JC, Lopes-Cendes I, Prada PO. Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis. Int J Obes (Lond) 2016; 41:268-278. [PMID: 27733761 DOI: 10.1038/ijo.2016.174] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 08/21/2016] [Accepted: 09/09/2016] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To investigate whether the Cdc2-like kinase 2 (CLK2) is expressed in hypothalamic neurons and if it is, whether the hypothalamic CLK2 has a role in the regulation of energy balance. SUBJECTS Swiss mice on chow or high-fat diet (HFD) and db/db mice on chow diet were used to address the role of CLK2 in the hypothalamus. RESULTS Hypothalamic CLK2Thr343 phosphorylation, which induces CLK2 activity, is regulated in vivo by refeeding, insulin and leptin, in a PI3K (phosphoinositide 3-kinase)-dependent manner. The reduction of CLK2 expression in the hypothalamus, by chronic pharmacological inhibition with TG003 or by chronic knockdown with small interfering RNA was sufficient to abolish the anorexigenic effect of insulin and leptin, to increase body weight, fat mass, food intake and to decrease energy expenditure in mice on chow. In contrast, CLK2Thr343 phosphorylation in the hypothalamus in response to insulin, leptin or refeeding was impaired in mice on HFD or in db/db mice. Chronic CLK2 inhibition in the hypothalamus was associated with a slight increase in the fasting blood glucose levels, reduction in PEPCK (phosphoenolpyruvate carboxykinase) expression in the liver and enhanced glucose production from pyruvate, suggesting a regulation of hepatic glucose production. Further, overexpressing CLK2 in the mediobasal hypothalami of mice on HFD or in db/db mice by adenovirus partially reversed the obese phenotype. CONCLUSIONS Thus, our results suggest that protein CLK2 integrates some important hypothalamic pathways, and may be a promising molecule for new therapeutic approaches for obesity and diabetes.
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Affiliation(s)
- P G F Quaresma
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.,Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - L Weissmann
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.,Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - T M Zanotto
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.,Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - A C Santos
- Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - A H B de Matos
- Department of Medical Genetics, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - I C Furigo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - F M Simabuco
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - J Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - J C Bittencourt
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - I Lopes-Cendes
- Department of Medical Genetics, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - P O Prada
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.,Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.,School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
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32
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Yang H, Yang L. Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy. J Mol Endocrinol 2016; 57:R93-R108. [PMID: 27194812 DOI: 10.1530/jme-15-0316] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 05/18/2016] [Indexed: 12/11/2022]
Abstract
In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMP-dependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).
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Affiliation(s)
- Haihua Yang
- Division of EndocrinologyZhengzhou Children's Hospital, Zhengzhou, Henan, China
| | - Linghai Yang
- Department of PharmacologyUniversity of Washington, Seattle, Washington, USA
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33
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Mohamad M, Mitchell SJ, Wu LE, White MY, Cordwell SJ, Mach J, Solon‐Biet SM, Boyer D, Nines D, Das A, Catherine Li S, Warren A, Hilmer SN, Fraser R, Sinclair DA, Simpson SJ, Cabo R, Le Couteur DG, Cogger VC. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance. Aging Cell 2016; 15:706-15. [PMID: 27095270 PMCID: PMC4933657 DOI: 10.1111/acel.12481] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2016] [Indexed: 12/16/2022] Open
Abstract
While age‐related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole‐body insulin handling and its role in age‐related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called ‘fenestrations’ are essential for insulin transfer across the liver sinusoidal endothelium and that age‐related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long‐term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age‐related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metabolism and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age‐related insulin resistance.
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Affiliation(s)
- Mashani Mohamad
- Ageing and Alzheimers Institute Centre for Education and Research on Ageing University of Sydney and Concord Hospital Sydney NSW Australia
- ANZAC Research Institute University of Sydney and Concord Hospital Sydney NSW Australia
- Faculty of Pharmacy Universiti Teknologi MARA Selangor Malaysia
| | - Sarah Jayne Mitchell
- Translational Gerontology Branch National Institute on Aging National Institutes of Health Baltimore MD USA
| | - Lindsay Edward Wu
- Laboratory for Ageing Research School of Medical Sciences University of New South Wales Sydney NSW Australia
| | | | | | - John Mach
- Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney Sydney NSW Australia
| | - Samantha Marie Solon‐Biet
- Ageing and Alzheimers Institute Centre for Education and Research on Ageing University of Sydney and Concord Hospital Sydney NSW Australia
- ANZAC Research Institute University of Sydney and Concord Hospital Sydney NSW Australia
- Charles Perkins Centre University of Sydney Sydney NSW Australia
| | - Dawn Boyer
- Translational Gerontology Branch National Institute on Aging National Institutes of Health Baltimore MD USA
| | - Dawn Nines
- Translational Gerontology Branch National Institute on Aging National Institutes of Health Baltimore MD USA
| | - Abhirup Das
- Laboratory for Ageing Research School of Medical Sciences University of New South Wales Sydney NSW Australia
| | - Shi‐Yun Catherine Li
- Laboratory for Ageing Research School of Medical Sciences University of New South Wales Sydney NSW Australia
| | - Alessandra Warren
- Ageing and Alzheimers Institute Centre for Education and Research on Ageing University of Sydney and Concord Hospital Sydney NSW Australia
- ANZAC Research Institute University of Sydney and Concord Hospital Sydney NSW Australia
| | - Sarah Nicole Hilmer
- Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney Sydney NSW Australia
| | - Robin Fraser
- Department of Pathology University of Otago Christchurch New Zealand
| | - David Andrew Sinclair
- Laboratory for Ageing Research School of Medical Sciences University of New South Wales Sydney NSW Australia
- Department of Genetics Harvard Medical School Boston MA USA
| | | | - Rafael Cabo
- Translational Gerontology Branch National Institute on Aging National Institutes of Health Baltimore MD USA
| | - David George Le Couteur
- Ageing and Alzheimers Institute Centre for Education and Research on Ageing University of Sydney and Concord Hospital Sydney NSW Australia
- ANZAC Research Institute University of Sydney and Concord Hospital Sydney NSW Australia
- Charles Perkins Centre University of Sydney Sydney NSW Australia
| | - Victoria Carroll Cogger
- Ageing and Alzheimers Institute Centre for Education and Research on Ageing University of Sydney and Concord Hospital Sydney NSW Australia
- ANZAC Research Institute University of Sydney and Concord Hospital Sydney NSW Australia
- Charles Perkins Centre University of Sydney Sydney NSW Australia
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34
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Singh P, Irwin DM. Contrasting Patterns in the Evolution of Vertebrate MLX Interacting Protein (MLXIP) and MLX Interacting Protein-Like (MLXIPL) Genes. PLoS One 2016; 11:e0149682. [PMID: 26910886 PMCID: PMC4766361 DOI: 10.1371/journal.pone.0149682] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/03/2016] [Indexed: 01/09/2023] Open
Abstract
ChREBP and MondoA are glucose-sensitive transcription factors that regulate aspects of energy metabolism. Here we performed a phylogenomic analysis of Mlxip (encoding MondoA) and Mlxipl (encoding ChREBP) genes across vertebrates. Analysis of extant Mlxip and Mlxipl genes suggests that the most recent common ancestor of these genes was composed of 17 coding exons. Single copy genes encoding both ChREBP and MondoA, along with their interacting partner Mlx, were found in diverse vertebrate genomes, including fish that have experienced a genome duplication. This observation suggests that a single Mlx gene has been retained to maintain coordinate regulation of ChREBP and MondoA. The ChREBP-β isoform, the more potent and constitutively active isoform, appeared with the evolution of tetrapods and is absent from the Mlxipl genes of fish. Evaluation of the conservation of ChREBP and MondoA sequences demonstrate that MondoA is better conserved and potentially mediates more ancient function in glucose metabolism.
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Affiliation(s)
- Parmveer Singh
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - David M. Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
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Choi K, Weber JM. Coping with an exogenous glucose overload: glucose kinetics of rainbow trout during graded swimming. Am J Physiol Regul Integr Comp Physiol 2015; 310:R493-501. [PMID: 26719305 DOI: 10.1152/ajpregu.00330.2015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 12/29/2015] [Indexed: 11/22/2022]
Abstract
This study examines how chronically hyperglycemic rainbow trout modulate glucose kinetics in response to graded exercise up to critical swimming speed (Ucrit), with or without exogenous glucose supply. Our goals were 1) to quantify the rates of hepatic glucose production (Ra glucose) and disposal (Rd glucose) during graded swimming, 2) to determine how exogenous glucose affects the changes in glucose fluxes caused by exercise, and 3) to establish whether exogenous glucose modifies Ucrit or the cost of transport. Results show that graded swimming causes no change in Ra and Rd glucose at speeds below 2.5 body lengths per second (BL/s), but that glucose fluxes may be stimulated at the highest speeds. Excellent glucoregulation is also achieved at all exercise intensities. When exogenous glucose is supplied during exercise, trout suppress hepatic production from 16.4 ± 1.6 to 4.1 ± 1.7 μmol·kg(-1)·min(-1) and boost glucose disposal to 40.1 ± 13 μmol·kg(-1)·min(-1). These responses limit the effects of exogenous glucose to a 2.5-fold increase in glycemia, whereas fish showing no modulation of fluxes would reach dangerous levels of 114 mM of blood glucose. Exogenous glucose reduces metabolic rate by 16% and, therefore, causes total cost of transport to decrease accordingly. High glucose availability does not improve Ucrit because the fish are unable to take advantage of this extra fuel during maximal exercise and rely on tissue glycogen instead. In conclusion, trout have a remarkable ability to adjust glucose fluxes that allows them to cope with the cumulative stresses of a glucose overload and graded exercise.
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Affiliation(s)
- Kevin Choi
- Biology Department, University of Ottawa, Ottawa, Ontario, Canada
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36
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Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin. Neurobiol Aging 2015; 39:19-24. [PMID: 26923398 DOI: 10.1016/j.neurobiolaging.2015.11.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 10/13/2015] [Accepted: 11/11/2015] [Indexed: 11/20/2022]
Abstract
Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important physiological differences between these cohorts.
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Affiliation(s)
- Dale S Edgerton
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
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38
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Choi K, Weber JM. Pushing the limits of glucose kinetics: how rainbow trout cope with a carbohydrate overload. J Exp Biol 2015; 218:2873-80. [DOI: 10.1242/jeb.125716] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/08/2015] [Indexed: 01/11/2023]
Abstract
Rainbow trout are generally considered as poor glucoregulators. To evaluate this statement, exogenous glucose was administered to chronically hyperglycemic fish at twice the endogenous rate of hepatic production, and their ability to modulate glucose fluxes was tested. Our goals were to determine: (1) whether hyperglycemic fish maintain higher glucose fluxes than normal; (2) whether they can lower hepatic production (Ra glucose) or stimulate disposal (Rd glucose) to cope with a carbohydrate overload; and (3) an estimate of the relative importance of glucose as an oxidative fuel. Results show that hyperglycemic trout sustain elevated baseline Ra and Rd glucose of 10.6±0.1 µmol kg−1 min−1 (or 30% above normal). If 50% of Rd was oxidized as in mammals, glucose could account from 36 to 100% of metabolic rate when exogenous glucose is supplied. In response to exogenous glucose, rainbow trout can completely suppress hepatic glucose production and increase disposal by 2.6-fold, even with chronically elevated baseline fluxes. Such large changes in fluxes limit the increase in blood glucose to 2.5-fold and are probably mediated by the effects of insulin on glucose transporters 2 and 4 and on key enzymes of carbohydrate metabolism. Without this strong and rapid modulation of glucose kinetics, glycemia would rise 4 times faster to reach dangerous levels exceeding 100 mmol l−1. Such responses are typical of mammals, but rather unexpected for an ectotherm. The impressive plasticity of glucose kinetics demonstrated here suggests that trout have a much better glucoregulatory capacity than usually portrayed in the literature.
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Affiliation(s)
- Kevin Choi
- Biology, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5
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Routh VH, Hao L, Santiago AM, Sheng Z, Zhou C. Hypothalamic glucose sensing: making ends meet. Front Syst Neurosci 2014; 8:236. [PMID: 25540613 PMCID: PMC4261699 DOI: 10.3389/fnsys.2014.00236] [Citation(s) in RCA: 131] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 11/26/2014] [Indexed: 01/12/2023] Open
Abstract
The neuroendocrine system governs essential survival and homeostatic functions. For example, growth is needed for development, thermoregulation maintains optimal core temperature in a changing environment, and reproduction ensures species survival. Stress and immune responses enable an organism to overcome external and internal threats while the circadian system regulates arousal and sleep such that vegetative and active functions do not overlap. All of these functions require a significant portion of the body's energy. As the integrator of the neuroendocrine system, the hypothalamus carefully assesses the energy status of the body in order to appropriately partition resources to provide for each system without compromising the others. While doing so the hypothalamus must ensure that adequate glucose levels are preserved for brain function since glucose is the primary fuel of the brain. To this end, the hypothalamus contains specialized glucose sensing neurons which are scattered throughout the nuclei controlling distinct neuroendocrine functions. We hypothesize that these neurons play a key role in enabling the hypothalamus to partition energy to meet these peripheral survival needs without endangering the brain's glucose supply. This review will first describe the varied mechanisms underlying glucose sensing in neurons within discrete hypothalamic nuclei. We will then evaluate the way in which peripheral energy status regulates glucose sensitivity. For example, during energy deficit such as fasting specific hypothalamic glucose sensing neurons become sensitized to decreased glucose. This increases the gain of the information relay when glucose availability is a greater concern for the brain. Finally, changes in glucose sensitivity under pathological conditions (e.g., recurrent insulin-hypoglycemia, diabetes) will be addressed. The overall goal of this review is to place glucose sensing neurons within the context of hypothalamic control of neuroendocrine function.
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Affiliation(s)
- Vanessa H Routh
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University Newark, NJ, USA
| | - Lihong Hao
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University Newark, NJ, USA ; Department of Pharmacology and Physiology and Graduate School of the Biomedical Sciences, New Jersey Medical School, Rutgers University Newark, NJ, USA
| | - Ammy M Santiago
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University Newark, NJ, USA ; Department of Pharmacology and Physiology and Graduate School of the Biomedical Sciences, New Jersey Medical School, Rutgers University Newark, NJ, USA
| | - Zhenyu Sheng
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University Newark, NJ, USA
| | - Chunxue Zhou
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University Newark, NJ, USA ; Department of Pharmacology and Physiology and Graduate School of the Biomedical Sciences, New Jersey Medical School, Rutgers University Newark, NJ, USA
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