|
1
|
Luo Y, Ma W, Cheng S, Yuan T, Li J, Hao H, Liu K, Zeng M, Pan Y. Transplantation of Cold-Stimulated Subcutaneous Adipose Tissue Improves Fat Retention and Recipient Metabolism. Aesthet Surg J 2024; 44:NP486-NP500. [PMID: 38518754 DOI: 10.1093/asj/sjae070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/29/2024] [Accepted: 03/12/2024] [Indexed: 03/24/2024] Open
Abstract
BACKGROUND Induction of beige fat for grafting is an emerging transplantation strategy. However, safety concerns associated with pharmaceutical interventions limit its wider application. Moreover, because beige fat is a special type of fat with strong metabolic functions, its effect on the metabolism of recipients after grafting has not been explored in the plastic surgery domain. OBJECTIVES The aim of this study was to explore whether cold-induced inguinal white adipose tissue (iWAT) transplantation has a higher retention rate and beneficial effects on recipient metabolism. METHODS C57/BL6 mice were subjected to cold stimulation for 48 hours to induce the browning of iWAT and harvested immediately. Subsequently, each mouse received a transplant of 0.2 mL cold-induced iWAT or normal iWAT. Fat grafts and recipients' iWAT, epididymal adipose tissue, and brown adipose tissue were harvested at 8 weeks after operation. Immunofluorescence staining, real-time polymerase chain reaction, and western blot were used for histological and molecular analysis. RESULTS Cold-induced iWAT grafting had a higher mean [standard error of the mean] retention rate (67.33% [1.74%] vs 55.83% [2.94%], P < .01) and more satisfactory structural integrity than normal iWAT. Histological changes identified improved adipose tissue homeostasis after cold challenge, including abundant smaller adipocytes, higher levels of adipogenesis, angiogenesis, and proliferation, but lower levels of fibrosis. More importantly, cold-induced iWAT grafting suppressed the inflammation of epididymal adipose tissue caused by conventional fat grafting, and activated the glucose metabolism and thermogenic activity of recipients' adipose tissues. CONCLUSIONS Cold-induced iWAT grafting is an effective nonpharmacological intervention strategy to improve the retention rate and homeostasis of grafts. Furthermore, it improves the adverse effects caused by traditional fat grafting, while also conferring metabolic benefits.
Collapse
|
|
2
|
Bahadoran Z, Mirmiran P, Ghasemi A. Adipose organ dysfunction and type 2 diabetes: Role of nitric oxide. Biochem Pharmacol 2024; 221:116043. [PMID: 38325496 DOI: 10.1016/j.bcp.2024.116043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/07/2024] [Accepted: 02/01/2024] [Indexed: 02/09/2024]
Abstract
Adipose organ, historically known as specialized lipid-handling tissue serving as the long-term fat depot, is now appreciated as the largest endocrine organ composed of two main compartments, i.e., subcutaneous and visceral adipose tissue (AT), madding up white and beige/brown adipocytes. Adipose organ dysfunction manifested as maldistribution of the compartments, hypertrophic, hypoxic, inflamed, and insulin-resistant AT, contributes to the development of type 2 diabetes (T2D). Here, we highlight the role of nitric oxide (NO·) in AT (dys)function in relation to developing T2D. The key aspects determining lipid and glucose homeostasis in AT depend on the physiological levels of the NO· produced via endothelial NO· synthases (eNOS). In addition to decreased NO· bioavailability (via decreased expression/activity of eNOS or scavenging NO·), excessive NO· produced by inducible NOS (iNOS) in response to hypoxia and AT inflammation may be a critical interfering factor diverting NO· signaling to the formation of reactive oxygen and nitrogen species, resulting in AT and whole-body metabolic dysfunction. Pharmacological approaches boosting AT-NO· availability at physiological levels (by increasing NO· production and its stability), as well as suppression of iNOS-NO· synthesis, are potential candidates for developing NO·-based therapeutics in T2D.
Collapse
Affiliation(s)
- Zahra Bahadoran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
3
|
Davis S, Hocking S, Watt MJ, Gunton JE. Metabolic effects of lipectomy and of adipose tissue transplantation. Obesity (Silver Spring) 2023; 31:7-19. [PMID: 36479639 PMCID: PMC10946570 DOI: 10.1002/oby.23601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/10/2022] [Accepted: 08/15/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The goal of this study was to review the metabolic effects of fat transplantation. METHODS Fat (adipose tissue [AT]) transplantation has been performed extensively for many years in the cosmetic reconstruction industry. However, not all fats are equal. White, brown, and beige AT differ in energy storage and use. Brown and beige AT consume glucose and lipids for thermogenesis and, theoretically, may provide greater metabolic benefit in transplantation. Here, the authors review the metabolic effects of AT transplantation. RESULTS Removal of subcutaneous human AT does not have beneficial metabolic effects. Most studies find no benefit from visceral AT transplantation and some studies report harmful effects. In contrast, transplantation of inguinal or subcutaneous AT in mice has positive effects. Brown AT transplant studies have variable results depending on the model but most show benefit. CONCLUSIONS Many technical improvements have optimized fat grafting and transplantation in cosmetic surgery. Transplantation of subcutaneous AT has the potential for significant metabolic benefits, although there are few studies in humans or using human AT. Brown AT transplantation is beneficial but not readily feasible in humans thus ex vivo "beiging" may be a useful strategy. AT transplantation may provide clinical benefits in metabolic disorders, especially in the setting of lipodystrophy.
Collapse
Affiliation(s)
- Sarah Davis
- Centre for Diabetes, Obesity and Endocrinology ResearchThe Westmead Institute for Medical Research, The University of SydneySydneyNew South WalesAustralia
- Faculty of Medicine and HealthThe University of SydneySydneyNew South WalesAustralia
| | - Samantha Hocking
- Faculty of Medicine and HealthThe University of SydneySydneyNew South WalesAustralia
- Department of EndocrinologyRoyal Prince Alfred HospitalSydneyNew South WalesAustralia
| | - Matthew J. Watt
- Department of Anatomy and PhysiologyUniversity of MelbourneMelbourneVictoriaAustralia
| | - Jenny E. Gunton
- Centre for Diabetes, Obesity and Endocrinology ResearchThe Westmead Institute for Medical Research, The University of SydneySydneyNew South WalesAustralia
- Faculty of Medicine and HealthThe University of SydneySydneyNew South WalesAustralia
- Department of Diabetes and EndocrinologyWestmead HospitalSydneyNew South WalesAustralia
| |
Collapse
|
|
4
|
Fryklund C, Neuhaus M, Morén B, Borreguero-Muñoz A, Lundmark R, Stenkula KG. Expansion of the Inguinal Adipose Tissue Depot Correlates With Systemic Insulin Resistance in C57BL/6J Mice. Front Cell Dev Biol 2022; 10:942374. [PMID: 36158197 PMCID: PMC9489915 DOI: 10.3389/fcell.2022.942374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
To accommodate surplus energy, the adipose tissue expands by increasing adipocyte size (hypertrophy) and number (hyperplasia). The presence of hypertrophic adipocytes is a key characteristic of adipose tissue dysfunction. High-fat diet (HFD) fed C57BL/6J mice are a commonly used model to study obesity and obesity-related complications. In the present study, we have characterized adipose plasticity, at both the cellular and tissue level, by examining the temporal development of systemic insulin resistance and adiposity in response to HFD-feeding for 4, 8, and 12 weeks (4w, 8w, and 12w). Within the same time frame, we examined systemic metabolic flexibility and adipose plasticity when switching from HFD- to chow-diet during the last 2 weeks of diet intervention (referred to as the reverse (REV) group: 4wREV (2w HFD+2w chow), 8wREV (6w HFD+2w chow), 12wREV (10w HFD+2w chow)). In response to HFD-feeding over time, the 12w group had impaired systemic insulin sensitivity compared to both the 4w and 8w groups, accompanied by an increase in hypertrophic inguinal adipocytes and liver triglycerides. After reversing from HFD- to chow-feeding, most parameters were completely restored to chow control levels for 4wREV and 8wREV groups. In contrast, the 12wREV group had a significantly increased number of hypertrophic adipocytes, liver triglycerides accumulation, and impaired systemic insulin sensitivity compared to chow-fed mice. Further, image analysis at the single-cell level revealed a cell-size dependent organization of actin filaments for all feeding conditions. Indeed, the impaired adipocyte size plasticity in the 12wREV group was accompanied by increased actin filamentation and reduced insulin-stimulated glucose uptake compared with chow-fed mice. In summary, these results demonstrate that the C57BL/6J HFD-feeding model has a large capacity to restore adipocyte cell size and systemic insulin sensitivity, and that a metabolic tipping point occurs between 8 and 12w of HFD-feeding where this plasticity deteriorates. We believe these findings provide substantial understanding of C57BL/6J mice as an obesity model, and that an increased pool of hypertrophic ING adipocytes could contribute to aggravated insulin resistance.
Collapse
Affiliation(s)
- Claes Fryklund
- Department of Experimental Medical Science, Lund University, Lund, Sweden
- *Correspondence: Claes Fryklund,
| | - Mathis Neuhaus
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Björn Morén
- Department of Experimental Medical Science, Lund University, Lund, Sweden
- Integrative Medical Biology, Umeå University, Umeå, Sweden
| | | | | | - Karin G. Stenkula
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| |
Collapse
|
|
5
|
Lee JH, Ealey KN, Patel Y, Verma N, Thakkar N, Park SY, Kim JR, Sung HK. Characterization of adipose depot-specific stromal cell populations by single-cell mass cytometry. iScience 2022; 25:104166. [PMID: 35434565 PMCID: PMC9010757 DOI: 10.1016/j.isci.2022.104166] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/18/2022] [Accepted: 03/24/2022] [Indexed: 11/17/2022] Open
Abstract
The increased prevalence of obesity and metabolic diseases has heightened interest in adipose tissue biology and its potential as a therapeutic target. To better understand cellular heterogeneity and complexity of white adipose tissue (WAT), we employed cytometry by time-of-flight (CyTOF) to characterize immune and stromal cells in visceral and subcutaneous WAT depots under normal and high-fat diet feeding, by quantifying the expression levels of 32 surface marker proteins. We observed comparable proportions of immune cells in two WAT depots under steady state, but depot-distinct subtypes of adipose precursor cells (APC), suggesting differences in their adipogenic and fibrogenic potential. Furthermore, in addition to pro-inflammatory immune cell shifts, significant pro-fibrotic changes were observed in APCs under high-fat diet, suggesting that APCs are early responders to dietary challenges. We propose CyTOF as a complementary and alternative tool to current high-throughput single-cell transcriptomic analyses to better understand the function and plasticity of adipose tissue.
Application of CyTOF for cellular characterization in two adipose depots Adipose depot-distinct APC subpopulations APCs are early responders under obesogenic conditions to regulate WAT fibrosis
Collapse
Affiliation(s)
- Ju Hee Lee
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Kafi N. Ealey
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yash Patel
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Navkiran Verma
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Nikita Thakkar
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - So Young Park
- Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Jae-Ryong Kim
- Department of Physiology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
- Corresponding author
| | - Hoon-Ki Sung
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Corresponding author
| |
Collapse
|
|
6
|
CCR2/CCL2 and CMKLR1/RvE1 chemokines system levels are associated with insulin resistance in rheumatoid arthritis. PLoS One 2021; 16:e0246054. [PMID: 33508012 PMCID: PMC7842933 DOI: 10.1371/journal.pone.0246054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/13/2021] [Indexed: 01/10/2023] Open
Abstract
Rheumatoid arthritis (RA) has been associated with insulin resistance (IR). Due to an excess in storage of white adipose tissue, IR has an inflammatory process that overlaps with RA. This is performed by the activation/migration of monocytes carried out by the CCR2/CCL2 and CMKLR1/RvE1 chemokines systems. Furthermore, these can potentiate chronic inflammation which is the central axis in the immunopathogenesis of RA. We evaluated the association between the relative expression of CCR2 and CMKLR1 and the serum levels of their ligands CCL2 and RvE1, in the context of adiposity status with IR as a comorbidity in RA. We studied 138 controls and 138 RA-patients classified with and without IR. We evaluated adiposity, RA activity, IR status and immunometabolic profiles by routine methods. Insulin, CCL2 and RvE1 serum levels were determined by ELISA. Relative expression of CCR2, CMKLR1 and RPS28 as constitutive gene by SYBR green RT-qPCR and 2-ΔΔCT method. Increased measurements were observed of body adiposity and metabolic status as follows: RA with IR>control group with IR>RA without IR> control group without IR. CCR2 and CMKLR1 relative expression was increased in RA without IR versus control without IR. CCR2: 2.3- and 1.3-fold increase and CMKLR1: 3.5- and 2.7-fold increase, respectively. Whereas, CCR2 expression correlates with CMKLR1 expression (rho = 0.331) and IR status (rho = 0.497 to 0.548). CMKLR1 expression correlates with inflammation markers (rho = 0.224 to 0.418). CCL2 levels were increased in the RA groups but levels of RvE1 were increased in RA without IR. We conclude that in RA with IR, the chemokine receptors expression pattern showed a parallel increase with their respective ligands. RA and IR in conjunction with the pathological distribution of body fat mass might exacerbate chronic inflammation. These results suggest that high CCL2 levels and compensatory RvE1 levels might not be enough to resolve the inflammation by themselves.
Collapse
|
|
7
|
Tsiloulis T, Raajendiran A, Keenan SN, Ooi G, Taylor RA, Burton P, Watt MJ. Impact of human visceral and glutealfemoral adipose tissue transplant on glycemic control in a mouse model of diet-induced obesity. Am J Physiol Endocrinol Metab 2020; 319:E519-E528. [PMID: 32603261 DOI: 10.1152/ajpendo.00373.2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Regional distribution of adipose tissue is an important factor in conferring cardiometabolic risk and obesity-related morbidity. We tested the hypothesis that human visceral adipose tissue (VAT) impairs glucose homeostasis, whereas subcutaneous glutealfemoral adipose tissue (GFAT) protects against the development of impaired glucose homeostasis in mice. VAT and GFAT were collected from patients undergoing bariatric surgery and grafted onto the epididymal adipose tissue of weight- and age-matched severe, combined immunodeficient mice. SHAM mice underwent surgery without transplant of tissue. Mice were fed a high-fat diet after xenograft. Energy homeostasis, glucose metabolism, and insulin sensitivity were assessed 6 wk later. Xenograft of human adipose tissues was successful, as determined by histology, immunohistochemical evaluation of collagen deposition and angiogenesis, and maintenance of lipolytic function. Adipose tissue transplant did not affect energy expenditure, food intake, whole body substrate partitioning, or plasma free fatty acid, triglyceride, and insulin levels. Fasting blood glucose was significantly reduced in GFAT and VAT compared with SHAM, whereas glucose tolerance was improved only in mice transplanted with VAT compared with SHAM mice. This improvement was not associated with differences in whole body insulin sensitivity or plasma insulin between groups. Together, these data suggest that VAT improves glycemic control and GFAT does not protect against the development of high-fat diet-induced glucose intolerance. Hence, the intrinsic properties of VAT and GFAT do not necessarily explain the postulated negative and positive effects of these adipose tissue depots on metabolic health.
Collapse
Affiliation(s)
- Thomas Tsiloulis
- Department of Physiology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- Monash Biomedicine Discovery Institute; Metabolism, Diabetes and Obesity and Cancer Programs. Monash University, Clayton, Victoria, Australia
| | - Arthe Raajendiran
- Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Stacey N Keenan
- Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Geraldine Ooi
- Centre for Obesity Research and Education, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
| | - Renea A Taylor
- Department of Physiology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- Monash Biomedicine Discovery Institute; Metabolism, Diabetes and Obesity and Cancer Programs. Monash University, Clayton, Victoria, Australia
- Cancer Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Australia
| | - Paul Burton
- Centre for Obesity Research and Education, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
| | - Matthew J Watt
- Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| |
Collapse
|
|
8
|
Schöttl T, Pachl F, Giesbertz P, Daniel H, Kuster B, Fromme T, Klingenspor M. Proteomic and Metabolite Profiling Reveals Profound Structural and Metabolic Reorganization of Adipocyte Mitochondria in Obesity. Obesity (Silver Spring) 2020; 28:590-600. [PMID: 32034895 DOI: 10.1002/oby.22737] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 11/26/2019] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Previous studies have revealed decreased mitochondrial respiration in adipocytes of obese mice. This study aimed to identify the molecular underpinnings of altered mitochondrial metabolism in adipocytes. METHODS Untargeted proteomics of mitochondria isolated from adipocytes and metabolite profiling of adipose tissues were conducted in diet-induced obese (DIO) and lean mice. Subcutaneous and intra-abdominal adipose tissues were studied to depict depot-specific alterations. RESULTS In subcutaneous adipocytes of DIO mice, changes in proteins related to mitochondrial structure and function were observed. Mitochondrial proteins of the inner and outer membrane were strongly reduced, whereas proteins of key matrix metabolic pathways were increased in the obese versus lean state, as further substantiated by metabolite profiling. A pronounced decrease in the oxidative phosphorylation (OXPHOS) enzymatic equipment and cristae density of the inner membrane was identified. In intra-abdominal adipocytes, similar systematic downregulation of the OXPHOS machinery in obesity occurred, but there was no regulation of outer membrane or matrix proteins. CONCLUSIONS Protein components of the OXPHOS machinery are systematically downregulated in adipose tissues of DIO mice compared with lean mice. Loss of the mitochondrial OXPHOS capacity in adipocytes may aggravate the development of metabolic disease.
Collapse
Affiliation(s)
- Theresa Schöttl
- Chair of Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
- EKFZ-Else Kröner Fresenius Zentrum for Nutritional Medicine, Technical Universtiy of Munich, Freising, Germany
- ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany
| | - Fiona Pachl
- ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany
- Chair of Proteomics and Bioanalytics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Pieter Giesbertz
- Chair of Nutritional Physiology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Hannelore Daniel
- Chair of Nutritional Physiology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Bernhard Kuster
- ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany
- Chair of Proteomics and Bioanalytics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Tobias Fromme
- Chair of Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
- EKFZ-Else Kröner Fresenius Zentrum for Nutritional Medicine, Technical Universtiy of Munich, Freising, Germany
- ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
- EKFZ-Else Kröner Fresenius Zentrum for Nutritional Medicine, Technical Universtiy of Munich, Freising, Germany
- ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany
| |
Collapse
|
|
9
|
Abstract
PURPOSE OF REVIEW Obesity is a major risk factor for type 2 diabetes. Although adipose tissue allows storage of excess calories in periods of overnutrition, in obesity, adipose tissue metabolism becomes dysregulated and can promote metabolic diseases. This review discusses recent advances in understandings how adipocyte metabolism impacts metabolic homeostasis. RECENT FINDINGS The ability of adipocytes to synthesize lipids from glucose is a marker of metabolic fitness, e.g., low de novo lipogenesis (DNL) in adipocytes correlates with insulin resistance in obesity. Adipocyte DNL may promote synthesis of special "insulin sensitizing" signaling lipids that act hormonally. However, each metabolic intermediate in the DNL pathway (i.e., citrate, acetyl-CoA, malonyl-CoA, and palmitate) also has second messenger functions. Mounting evidence suggests these signaling functions may also be important for maintaining healthy adipocytes. While adipocyte DNL contributes to lipid storage, lipid precursors may have additional second messenger functions critical for maintaining adipocyte health, and thus systemic metabolic homeostasis.
Collapse
Affiliation(s)
- Wen-Yu Hsiao
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA, 01605, USA
| | - David A Guertin
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA, 01605, USA.
| |
Collapse
|
|
10
|
Ghanemi A, Melouane A, Yoshioka M, St-Amand J. Secreted protein acidic and rich in cysteine and bioenergetics: Extracellular matrix, adipocytes remodeling and skeletal muscle metabolism. Int J Biochem Cell Biol 2019; 117:105627. [PMID: 31589923 DOI: 10.1016/j.biocel.2019.105627] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 09/20/2019] [Accepted: 10/01/2019] [Indexed: 12/18/2022]
Abstract
The extracellular matrix (ECM) remodeling plays important roles in both adipocytes shape/expansion remodeling and the skeletal muscle (SM) metabolism. Secreted protein acidic and rich in cysteine (SPARC) is expressed in divers tissues including adipose tissue (AT) and SM where it impacts a variety of remodeling as well as metabolic functions. SPARC, also known as osteonectin or BM-40, is a glycoprotein associated with the ECM. Numerous researches attempted to elucidate the implications of SPARC in these two key metabolic tissues under different conditions. Whereas SPARC deficiency tends to shape the remodeling of the adipocytes and the fat distribution, this deficiency decreases SM metabolic properties. On the other hand, SPARC seems to be an enhancer of the metabolism and a mediator of the exercise-induced adaptation in the SM and as well as an adipogenesis inhibitor. Some findings about the SPARC effects on AT and SM seem "contradictory" in terms of tissue development and energy profile therefore highlighting the mechanistic role of SPARC in both is a priority. Yet, within this review, we expose selected researches and compare the results. We conclude with explanations to "reconcile" the different observations, hypothesize the feedback and regulatory character of SPARC and put its roles within the energetic and structural maps of both adipocytes and myocytes in homeostasis and in situations such as obesity or exercise. These properties explain the modifications and the remodeling seen in AT and SM undergoing adaptive changes (obesity, exercise, etc.) and represent a starting point for precise therapeutic targeting of SPARC-related pathways is conditions such as obesity, sarcopenia and diabetes.
Collapse
Affiliation(s)
- Abdelaziz Ghanemi
- Functional Genomics Laboratory, CREMI, Québec Genome Center, CHUL-CHU de Québec Research Center, Québec, Québec G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Québec G1V 0A6, Canada
| | - Aicha Melouane
- Functional Genomics Laboratory, CREMI, Québec Genome Center, CHUL-CHU de Québec Research Center, Québec, Québec G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Québec G1V 0A6, Canada
| | - Mayumi Yoshioka
- Functional Genomics Laboratory, CREMI, Québec Genome Center, CHUL-CHU de Québec Research Center, Québec, Québec G1V 4G2, Canada
| | - Jonny St-Amand
- Functional Genomics Laboratory, CREMI, Québec Genome Center, CHUL-CHU de Québec Research Center, Québec, Québec G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Québec G1V 0A6, Canada.
| |
Collapse
|
|
11
|
Silva KR, Baptista LS. Adipose-derived stromal/stem cells from different adipose depots in obesity development. World J Stem Cells 2019; 11:147-166. [PMID: 30949294 PMCID: PMC6441940 DOI: 10.4252/wjsc.v11.i3.147] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 01/27/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023] Open
Abstract
The increasing prevalence of obesity is alarming because it is a risk factor for cardiovascular and metabolic diseases (such as type 2 diabetes). The occurrence of these comorbidities in obese patients can arise from white adipose tissue (WAT) dysfunctions, which affect metabolism, insulin sensitivity and promote local and systemic inflammation. In mammals, WAT depots at different anatomical locations (subcutaneous, preperitoneal and visceral) are highly heterogeneous in their morpho-phenotypic profiles and contribute differently to homeostasis and obesity development, depending on their ability to trigger and modulate WAT inflammation. This heterogeneity is likely due to the differential behavior of cells from each depot. Numerous studies suggest that adipose-derived stem/stromal cells (ASC; referred to as adipose progenitor cells, in vivo) with depot-specific gene expression profiles and adipogenic and immunomodulatory potentials are keys for the establishment of the morpho-functional heterogeneity between WAT depots, as well as for the development of depot-specific responses to metabolic challenges. In this review, we discuss depot-specific ASC properties and how they can contribute to the pathophysiology of obesity and metabolic disorders, to provide guidance for researchers and clinicians in the development of ASC-based therapeutic approaches.
Collapse
Affiliation(s)
- Karina Ribeiro Silva
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology, Duque de Caxias, RJ 25250-020, Brazil
- Post-Graduation Program of Biotechnology, National Institute of Metrology, Quality and Technology, Duque de Caxias, RJ 25250-020, Brazil
| | - Leandra Santos Baptista
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology, Duque de Caxias, RJ 25250-020, Brazil
- Post-Graduation Program of Biotechnology, National Institute of Metrology, Quality and Technology, Duque de Caxias, RJ 25250-020, Brazil
- Multidisciplinary Center for Biological Research (Numpex-Bio), Federal University of Rio de Janeiro Campus Duque de Caxias, Duque de Caxias, RJ 25245-390, Brazil
| |
Collapse
|
|
12
|
Wang H, Xu PF, Li JY, Liu XJ, Wu XY, Xu F, Xie BC, Huang XM, Zhou ZH, Kayoumu A, Liu G, Huang W. Adipose tissue transplantation ameliorates lipodystrophy-associated metabolic disorders in seipin-deficient mice. Am J Physiol Endocrinol Metab 2019; 316:E54-E62. [PMID: 30457912 DOI: 10.1152/ajpendo.00180.2018] [Citation(s) in RCA: 17] [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] [Indexed: 12/28/2022]
Abstract
Seipin deficiency is responsible for type 2 congenital generalized lipodystrophy with severe loss of adipose tissue and can lead to hepatic steatosis, insulin resistance (IR), and dyslipidemia in humans. Adipose tissue secretes many adipokines that are central to the regulation of metabolism. In this study, we investigated whether transplantation of normal adipose tissue could ameliorate severe hepatic steatosis, IR, and dyslipidemia in lipoatrophic seipin knockout (SKO) mice. Normal adipose tissue from wild-type mice was transplanted into 6-wk-old SKO mice. At 4 mo after adipose tissue transplantation (AT), the transplanted fat survived with detectable blood vessels, and the reduced levels of plasma leptin, a major adipokine, were dramatically increased. Severe hepatic steatosis, IR, and dyslipidemia in SKO mice were ameliorated after AT. In addition, abnormal hepatic lipogenesis and β-oxidation gene expression in SKO mice were improved after AT. Our results suggest that AT may be an effective treatment to improve lipodystrophy-associated metabolic disorders.
Collapse
Affiliation(s)
- Huan Wang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University , Beijing , China
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Peng-Fei Xu
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
- Institute of Military Training Related Medical Science of PLA, 150th Central Hospital of PLA , Luoyang, Henan , China
| | - Jing-Yi Li
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Xue-Jing Liu
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Xiao-Yue Wu
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Fang Xu
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Bei-Chen Xie
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Xiao-Min Huang
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Zi-Hao Zhou
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Abudurexiti Kayoumu
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - George Liu
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| | - Wei Huang
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center , Beijing , China
| |
Collapse
|
|
13
|
Iñiguez M, Pérez-Matute P, Villanueva-Millán MJ, Recio-Fernández E, Roncero-Ramos I, Pérez-Clavijo M, Oteo JA. Agaricus bisporus supplementation reduces high-fat diet-induced body weight gain and fatty liver development. J Physiol Biochem 2018; 74:635-646. [PMID: 30288689 DOI: 10.1007/s13105-018-0649-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 09/12/2018] [Indexed: 02/06/2023]
Abstract
Obesity is a global epidemic characterized not only by excessive fat deposition but also by important complications such as nonalcoholic liver steatosis. Beneficial antiobesogenic effects have been described for some mushrooms. The current study aimed to demonstrate the protective effect of Agaricus bisporus (AB) supplementation against the metabolic alterations induced by high-fat-diet (HFD) feeding. Eight-week-old C57BL/6J mice were fed for 10 weeks with one of the following diets: (1) control diet (n = 7), (2) HFD (n = 7), (3) HFD supplemented with 5% AB (n = 9), and (4) HFD supplemented with 10% AB (n = 9). A pair-fed group was also included for the 10% AB group (n = 6). The impact of AB supplementation on food intake, body weight gain, and liver and fat pad weights was examined. Biochemical, histological, and molecular parameters were also analyzed. Dietary supplementation with 10% AB reduced the HFD-induced increase in body, epididymal, and mesenteric fat weights (p < 0.01, p < 0.05, and p < 0.05, respectively). Supplementation with AB also reduced liver damage in a dose-dependent manner (p < 0.01 and p < 0.001). This effect was confirmed by histological analysis that showed that liver steatosis was markedly reduced in mice fed with AB. The beneficial properties of 10% AB supplementation appear to be mediated through a decrease in food intake and via stimulation of mesenteric and hepatic free-fatty acid beta-oxidation, along with a decrease in epidydimal and hepatic expression of CD36. In conclusion, supplementation with AB prevents excessive body weight gain and liver steatosis induced by HFD consumption.
Collapse
Affiliation(s)
- María Iñiguez
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3rd floor, 26006, Logroño, La Rioja, Spain
| | - Patricia Pérez-Matute
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3rd floor, 26006, Logroño, La Rioja, Spain.
| | - María Jesús Villanueva-Millán
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3rd floor, 26006, Logroño, La Rioja, Spain
| | - Emma Recio-Fernández
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3rd floor, 26006, Logroño, La Rioja, Spain
| | - Irene Roncero-Ramos
- Mushroom Technological Research Center of La Rioja (CTICH), Autol, La Rioja, Spain
| | | | - José-Antonio Oteo
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3rd floor, 26006, Logroño, La Rioja, Spain.,Infectious Diseases Department, Hospital San Pedro, Logroño, La Rioja, Spain
| |
Collapse
|
|
14
|
Yaneselli KM, Kuhl CP, Terraciano PB, de Oliveira FS, Pizzato SB, Pazza K, Magrisso AB, Torman V, Rial A, Moreno M, Llambí S, Cirne-Lima E, Maisonnave J. Comparison of the characteristics of canine adipose tissue-derived mesenchymal stem cells extracted from different sites and at different passage numbers. J Vet Sci 2018; 19:13-20. [PMID: 28693305 PMCID: PMC5799390 DOI: 10.4142/jvs.2018.19.1.13] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 04/25/2017] [Accepted: 05/05/2017] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have desirable characteristics for use in therapy in animal models and veterinary medicine, due to their capacity of inducing tissue regeneration and immunomodulation. The objective of this study was to evaluate the differences between canine adipose tissue-derived MSCs (AD-MSCs) extracted from subcutaneous (Sc) and visceral (Vs) sites. Surface antigenic markers, in vitro differentiation, and mineralized matrix quantification of AD-MSCs at different passages (P4, P6, and P8) were studied. Immunophenotypic analysis showed that AD-MSCs from both sites were CD44+, CD90+, and CD45-. Moreover, they were able, in vitro, to differentiate into fat, cartilage, and bone. Sc-AD-MSCs preserve in vitro multipotentiality up to P8, but Vs-AD-MSCs only tri-differentiated up to P4. In addition, compared to Vs-AD-MSCs, Sc-AD-MSCs had greater capacity for in vitro mineralized matrix synthesis. In conclusion, Sc-AD-MSCs have advantages over Vs-AD-MSCs, as Sc AD-MSCs preserve multipotentiality during a greater number of passages, have more osteogenic potential, and require less invasive extraction.
Collapse
Affiliation(s)
- Kevin M Yaneselli
- Laboratory of Immunology, Department of Microbiological Science, Faculty of Veterinary, Universidad de la República, Montevideo 11600, Uruguay
| | - Cristiana P Kuhl
- Laboratory of Embryology and Cellular Differentiation, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Paula B Terraciano
- Laboratory of Embryology and Cellular Differentiation, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Fernanda S de Oliveira
- Laboratory of Embryology and Cellular Differentiation, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Sabrina B Pizzato
- Laboratory of Embryology and Cellular Differentiation, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Kamila Pazza
- Laboratory of Embryology and Cellular Differentiation, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Alessandra B Magrisso
- Laboratory of Embryology and Cellular Differentiation, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Vanessa Torman
- Biostatistics, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Analía Rial
- Laboratory for Vaccine Research, Department of Biotechnology, Instituto de Higiene, Faculty of Medicine, Universidad de la República, Montevideo 11600, Uruguay
| | - María Moreno
- Laboratory for Vaccine Research, Department of Biotechnology, Instituto de Higiene, Faculty of Medicine, Universidad de la República, Montevideo 11600, Uruguay
| | - Silvia Llambí
- Laboratory of Genetics, Faculty of Veterinary, Universidad de la República, Montevideo 11600, Uruguay
| | - Elizabeth Cirne-Lima
- Laboratory of Embryology and Cellular Differentiation, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
| | - Jacqueline Maisonnave
- Laboratory of Immunology, Department of Microbiological Science, Faculty of Veterinary, Universidad de la República, Montevideo 11600, Uruguay
| |
Collapse
|
|
15
|
Clayton ZS, McCurdy CE. Short-term thermoneutral housing alters glucose metabolism and markers of adipose tissue browning in response to a high-fat diet in lean mice. Am J Physiol Regul Integr Comp Physiol 2018; 315:R627-R637. [PMID: 29791203 DOI: 10.1152/ajpregu.00364.2017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Systemic insulin resistance and glucose intolerance occur with as little as 3 days of a high-fat diet (HFD) in mice and humans; the mechanisms that initiate acute insulin resistance are unknown. Most laboratories house mice at 22°C, which is below their thermoneutral temperature (~30°C). Cold stress has been shown to increase white adipose tissue (WAT) browning, alter lipid trafficking, and impair immune function, whereas energy intake and expenditure decrease with increasing ambient temperature; importantly, dysregulation of these parameters has been strongly linked to obesity-induced insulin resistance. Therefore, we compared acute changes in glucose metabolism and the metabolic phenotype in lean mice in response to a control diet or HFD housed at standard vivarium (22°C) and thermoneutral (30°C) temperatures. Glucose intolerance occurred following 1 or 5 days of HFD and was independent of housing temperature or adiposity; however, the reduction in tissue-specific glucose clearance with HFD diverged by temperature with reduced brown adipose tissue (BAT) glucose uptake at 22°C but reduced soleus glucose uptake at 30°C. Fasting glucose, food intake, and energy expenditure were significantly lower at 30°C, independent of diet. Additionally, markers of browning in both BAT and inguinal subcutaneous WAT, but not perigonadal epididymal WAT, decreased at 30°C. Together, we find housing temperature has a significant impact on the cellular pathways that regulate glucose tolerance in response to an acute HFD exposure. Thus, even short-term changes in housing temperature should be highly considered in interpretation of metabolic studies in mice.
Collapse
Affiliation(s)
- Zachary S Clayton
- Department of Human Physiology, University of Oregon , Eugene, Oregon
| | - Carrie E McCurdy
- Department of Human Physiology, University of Oregon , Eugene, Oregon
| |
Collapse
|
|
16
|
A direct tissue-grafting approach to increasing endogenous brown fat. Sci Rep 2018; 8:7957. [PMID: 29785004 PMCID: PMC5962549 DOI: 10.1038/s41598-018-25866-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 04/24/2018] [Indexed: 12/20/2022] Open
Abstract
There is widespread evidence that increasing functional mass of brown adipose tissue (BAT) via browning of white adipose tissue (WAT) could potentially counter obesity and diabetes. However, most current approaches focus on administration of pharmacological compounds which expose patients to highly undesirable side effects. Here, we describe a simple and direct tissue-grafting approach to increase BAT mass through ex vivo browning of subcutaneous WAT, followed by re-implantation into the host; this cell-therapy approach could potentially act synergistically with existing pharmacological approaches. With this process, entitled "exBAT", we identified conditions, in both mouse and human tissue, that convert whole fragments of WAT to BAT via a single step and without unwanted off-target pharmacological effects. We show that ex vivo, exBAT exhibited UCP1 immunostaining, lipid droplet formation, and mitochondrial metabolic activity consistent with native BAT. In mice, exBAT exhibited a highly durable phenotype for at least 8 weeks. Overall, these results enable a simple and scalable tissue-grafting strategy, rather than pharmacological approaches, for increasing endogenous BAT and studying its effect on host weight and metabolism.
Collapse
|
|
17
|
Morales Drissi N, Romu T, Landtblom AM, Szakács A, Hallböök T, Darin N, Borga M, Leinhard OD, Engström M. Unexpected Fat Distribution in Adolescents With Narcolepsy. Front Endocrinol (Lausanne) 2018; 9:728. [PMID: 30574118 PMCID: PMC6292486 DOI: 10.3389/fendo.2018.00728] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 11/16/2018] [Indexed: 02/02/2023] Open
Abstract
Narcolepsy type 1 is a chronic sleep disorder with significantly higher BMI reported in more than 50% of adolescent patients, putting them at a higher risk for metabolic syndrome in adulthood. Although well-documented, the body fat distribution and mechanisms behind weight gain in narcolepsy are still not fully understood but may be related to the loss of orexin associated with the disease. Orexin has been linked to the regulation of brown adipose tissue (BAT), a metabolically active fat involved in energy homeostasis. Previous studies have used BMI and waist circumference to characterize adipose tissue increases in narcolepsy but none have investigated its specific distribution. Here, we examine adipose tissue distribution in 19 adolescent patients with narcolepsy type 1 and compare them to 17 of their healthy peers using full body magnetic resonance imaging (MRI). In line with previous findings we saw that the narcolepsy patients had more overall fat than the healthy controls, but contrary to our expectations there were no group differences in supraclavicular BAT, suggesting that orexin may have no effect at all on BAT, at least under thermoneutral conditions. Also, in line with previous reports, we observed that patients had more total abdominal adipose tissue (TAAT), however, we found that they had a lower ratio between visceral adipose tissue (VAT) and TAAT indicating a relative increase of subcutaneous abdominal adipose tissue (ASAT). This relationship between VAT and ASAT has been associated with a lower risk for metabolic disease. We conclude that while weight gain in adolescents with narcolepsy matches that of central obesity, the lower VAT ratio may suggest a lower risk of developing metabolic disease.
Collapse
Affiliation(s)
- Natasha Morales Drissi
- Department of Medical and Health Sciences (IMH), Linköping University, Linköping, Sweden
- Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
| | - Thobias Romu
- Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
- AMRA Medical AB, Linköping, Sweden
| | - Anne-Marie Landtblom
- Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
- Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Attilla Szakács
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tove Hallböök
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Niklas Darin
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Borga
- Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
- AMRA Medical AB, Linköping, Sweden
- Department of Biomedical Engineering (IMT), Linköping University, Linköping, Sweden
| | - Olof Dahlqvist Leinhard
- Department of Medical and Health Sciences (IMH), Linköping University, Linköping, Sweden
- Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
- AMRA Medical AB, Linköping, Sweden
| | - Maria Engström
- Department of Medical and Health Sciences (IMH), Linköping University, Linköping, Sweden
- Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
- *Correspondence: Maria Engström
| |
Collapse
|
|
18
|
Guilherme A, Pedersen DJ, Henchey E, Henriques FS, Danai LV, Shen Y, Yenilmez B, Jung D, Kim JK, Lodhi IJ, Semenkovich CF, Czech MP. Adipocyte lipid synthesis coupled to neuronal control of thermogenic programming. Mol Metab 2017; 6:781-796. [PMID: 28752043 PMCID: PMC5518709 DOI: 10.1016/j.molmet.2017.05.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 05/15/2017] [Accepted: 05/25/2017] [Indexed: 12/25/2022] Open
Abstract
Background The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood. Methods & results Here we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT). Induced deletion of FASN in white and brown adipocytes of mature mice (iAdFASNKO mice) enhanced glucose tolerance, UCP1 expression, and cAMP signaling in iWAT. Consistent with induction of adipose sympathetic nerve activity, iAdFASNKO mice displayed markedly increased neuronal tyrosine hydroxylase (TH) and neuropeptide Y (NPY) content in iWAT. In contrast, brown adipose tissue (BAT) of iAdFASNKO mice showed no increase in TH or NPY, nor did FASN deletion selectively in brown adipocytes (UCP1-FASNKO mice) cause these effects in iWAT. Conclusions These results demonstrate that downregulation of fatty acid synthesis via FASN depletion in white adipocytes of mature mice can stimulate neuronal signaling to control thermogenic programming in iWAT.
Inducible deletion of FASN in white adipocytes of mature mice enhances browning of iWAT. Inducible deletion of white adipocyte FASN in mature obese mice improves glucose tolerance. Loss of FASN in white adipocytes enhances sympathetic nerve outflow in iWAT. Crosstalk between adipocyte fat metabolism and neuronal stimulation of adipose tissue is proposed.
Collapse
Affiliation(s)
- Adilson Guilherme
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - David J Pedersen
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Elizabeth Henchey
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Felipe S Henriques
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Laura V Danai
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Yuefei Shen
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Batuhan Yenilmez
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - DaeYoung Jung
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Jason K Kim
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Irfan J Lodhi
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Clay F Semenkovich
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
| |
Collapse
|
|
19
|
Wicksteed B, Dickson LM. PKA Differentially Regulates Adipose Depots to Control Energy Expenditure. Endocrinology 2017; 158:464-466. [PMID: 28430917 PMCID: PMC5460779 DOI: 10.1210/en.2017-00038] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Accepted: 01/13/2017] [Indexed: 11/19/2022]
Affiliation(s)
- Barton Wicksteed
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; and
| | | |
Collapse
|
|
20
|
Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16. Nat Commun 2016; 7:11533. [PMID: 27240637 PMCID: PMC4895052 DOI: 10.1038/ncomms11533] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 04/06/2016] [Indexed: 01/22/2023] Open
Abstract
Visceral adiposity is strongly associated with metabolic disease risk, whereas
subcutaneous adiposity is comparatively benign. However, their relative
physiological importance in energy homeostasis remains unclear. Here, we show that
after 24-h fasting, the subcutaneous adipose tissue of mice acquires key properties
of visceral fat. During this fast-induced ‘visceralization',
upregulation of miR-149-3p directly targets PR domain containing 16 (PRDM16), a key
coregulatory protein required for the ‘browning' of white fat. In
cultured inguinal preadipocytes, overexpression of miR-149-3p promotes a
visceral-like switch during cell differentiation. Mice deficient in miR-149-3p
display an increase in whole-body energy expenditure, with enhanced thermogenesis of
inguinal fat. However, a visceral-like adipose phenotype is observed in inguinal
depots overexpressing miR-149-3p. These results indicate that in addition to the
capacity of ‘browning' to defend against hypothermia during cold
exposure, the subcutaneous adipose depot is also capable of ‘whitening'
to preserve energy during fasting, presumably to maintain energy balance, via
miR-149-3p-mediated regulation of PRDM16. Visceral adiposity is associated with metabolic diseases, whereas
subcutaneous adiposity is comparatively benign. Here, the authors report that
subcutaneous adipose tissue adopts visceral-like characteristics in response to
prolonged fasting, and show this is mediated by miR-149-3p and its target,
PRDM16.
Collapse
|
|
21
|
Dickson LM, Gandhi S, Layden BT, Cohen RN, Wicksteed B. Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health. Am J Physiol Regul Integr Comp Physiol 2016; 311:R79-88. [PMID: 27097660 DOI: 10.1152/ajpregu.00114.2016] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 04/18/2016] [Indexed: 01/09/2023]
Abstract
Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial function. PKA transduces the cAMP signal downstream of G protein-coupled receptors, which are being explored for therapeutic manipulation to reduce obesity and improve metabolic health. This study aimed to determine the overall physiological consequences of PKA activation in adipose tissue. Mice expressing an activated PKA catalytic subunit in adipose tissue (Adipoq-caPKA mice) showed increased PKA activity in subcutaneous, epididymal, and mesenteric white adipose tissue (WAT) depots and brown adipose tissue (BAT) compared with controls. Adipoq-caPKA mice weaned onto a high-fat diet (HFD) or switched to the HFD at 26 wk of age were protected from diet-induced weight gain. Metabolic health was improved, with enhanced insulin sensitivity, glucose tolerance, and β-cell function. Adipose tissue health was improved, with smaller adipocyte size and reduced macrophage engulfment of adipocytes. Using metabolic cages, we found that Adipoq-caPKA mice were shown to have increased energy expenditure, but no difference to littermate controls in physical activity or food consumption. Immunoblotting of adipose tissue showed increased expression of uncoupling protein-1 (UCP1) in BAT and dramatic UCP1 induction in subcutaneous WAT, but no induction in the visceral depots. Feeding a HFD increased PKA activity in epididymal WAT of wild-type mice compared with chow, but did not change PKA activity in subcutaneous WAT or BAT. This was associated with changes in PKA regulatory subunit expression. This study shows that adipose tissue PKA activity is sufficient to increase energy expenditure and indicates that PKA is a beneficial target in metabolic health.
Collapse
Affiliation(s)
- Lorna M Dickson
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Shriya Gandhi
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Brian T Layden
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Ronald N Cohen
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Barton Wicksteed
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois; Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and
| |
Collapse
|
|
22
|
Heterogeneity of white adipose tissue: molecular basis and clinical implications. Exp Mol Med 2016; 48:e215. [PMID: 26964831 PMCID: PMC4892883 DOI: 10.1038/emm.2016.5] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 11/29/2015] [Indexed: 02/08/2023] Open
Abstract
Adipose tissue is a highly heterogeneous endocrine organ. The heterogeneity among different anatomical depots stems from their intrinsic differences in cellular and physiological properties, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, insulin sensitivity, hormonal control, thermogenic ability and vascularization. Additional factors that influence adipose tissue heterogeneity are genetic predisposition, environment, gender and age. Under obese condition, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. For instance, individuals with central obesity are more susceptible to developing diabetes and cardiovascular complications, whereas those with peripheral obesity are more metabolically healthy. This review summarizes the clinical and mechanistic evidence for the depot-specific differences that give rise to different metabolic consequences, and provides therapeutic insights for targeted treatment of obesity.
Collapse
|
|
23
|
Harris RBS. In vivo evidence for unidentified leptin-induced circulating factors that control white fat mass. Am J Physiol Regul Integr Comp Physiol 2015; 309:R1499-511. [PMID: 26468261 DOI: 10.1152/ajpregu.00335.2015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/13/2015] [Indexed: 12/29/2022]
Abstract
Fat transplants increase body fat mass without changing the energy status of an animal and provide a tool for investigating control of total body fat. Early transplant studies found that small pieces of transplanted fat took on the morphology of the transplant recipient. Experiments described here tested whether this response was dependent upon expression of leptin receptors in either transplanted fat or the recipient mouse. Fat from leptin receptor deficient db/db mice or wild-type mice was placed subcutaneously in db/db mice. After 12 wk, cell size distribution in the transplant was the same as in endogenous fat of the recipient. Thus, wild-type fat cells, which express leptin receptors, were enlarged in a hyperleptinemic environment, indicating that leptin does not directly control adipocyte size. By contrast, db/db or wild-type fat transplanted into wild-type mice decreased in size, suggesting that a functional leptin system in the recipient is required for body fat mass to be controlled. In the final experiment, wild-type fat was transplanted into a db/db mouse parabiosed to either another db/db mouse to an ob/ob mouse or in control pairs in which both parabionts were ob/ob mice. Transplants increased in size in db/db-db/db pairs, decreased in db/db-ob/ob pairs and did not change in ob/ob-ob/ob pairs. We propose that leptin from db/db parabionts activated leptin receptors in their ob/ob partners. This, in turn, stimulated release of unidentified circulating factors, which travelled back to the db/db partner and acted on the transplant to reduce fat cell size.
Collapse
Affiliation(s)
- Ruth B S Harris
- Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia
| |
Collapse
|
|
24
|
Hocking SL, Stewart RL, Brandon AE, Suryana E, Stuart E, Baldwin EM, Kolumam GA, Modrusan Z, Junutula JR, Gunton JE, Medynskyj M, Blaber SP, Karsten E, Herbert BR, James DE, Cooney GJ, Swarbrick MM. Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice. Diabetologia 2015; 58:1587-600. [PMID: 25899451 DOI: 10.1007/s00125-015-3583-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 03/13/2015] [Indexed: 12/26/2022]
Abstract
AIMS/HYPOTHESIS Adipose tissue (AT) distribution is a major determinant of mortality and morbidity in obesity. In mice, intra-abdominal transplantation of subcutaneous AT (SAT) protects against glucose intolerance and insulin resistance (IR), but the underlying mechanisms are not well understood. METHODS We investigated changes in adipokines, tissue-specific glucose uptake, gene expression and systemic inflammation in male C57BL6/J mice implanted intra-abdominally with either inguinal SAT or epididymal visceral AT (VAT) and fed a high-fat diet (HFD) for up to 17 weeks. RESULTS Glucose tolerance was improved in mice receiving SAT after 6 weeks, and this was not attributable to differences in adiposity, tissue-specific glucose uptake, or plasma leptin or adiponectin concentrations. Instead, SAT transplantation prevented HFD-induced hepatic triacylglycerol accumulation and normalised the expression of hepatic gluconeogenic enzymes. Grafted fat displayed a significant increase in glucose uptake and unexpectedly, an induction of skeletal muscle-specific gene expression. Mice receiving subcutaneous fat also displayed a marked reduction in the plasma concentrations of several proinflammatory cytokines (TNF-α, IL-17, IL-12p70, monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-1β [ΜIP-1β]), compared with sham-operated mice. Plasma IL-17 and MIP-1β concentrations were reduced from as early as 4 weeks after transplantation, and differences in plasma TNF-α and IL-17 concentrations predicted glucose tolerance and insulinaemia in the entire cohort of mice (n = 40). In contrast, mice receiving visceral fat transplants were glucose intolerant, with increased hepatic triacylglycerol content and elevated plasma IL-6 concentrations. CONCLUSIONS/INTERPRETATION Intra-abdominal transplantation of subcutaneous fat reverses HFD-induced glucose intolerance, hepatic triacylglycerol accumulation and systemic inflammation in mice.
Collapse
Affiliation(s)
- Samantha L Hocking
- Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010, Sydney, NSW, Australia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Abstract
Obesity is associated with altered gut microbiota composition and impaired gut barrier function. These changes, together with interrelated mesenteric adipose tissue inflammation, result in increased release of pro-inflammatory cytokines, bacteria-derived factors, and lipids into the portal circulation, promoting the development of (hepatic) insulin resistance. Herein, the potential impact of obesity-related changes in gut and visceral adipose tissue biology on the development of insulin resistance and Type 2 diabetes is reviewed.
Collapse
Affiliation(s)
- Daniel Konrad
- Department of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland; Children's Research Center, University Children's Hospital, Zurich, Switzerland; and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Stephan Wueest
- Department of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland; Children's Research Center, University Children's Hospital, Zurich, Switzerland; and
| |
Collapse
|
|
26
|
Schöttl T, Kappler L, Braun K, Fromme T, Klingenspor M. Limited mitochondrial capacity of visceral versus subcutaneous white adipocytes in male C57BL/6N mice. Endocrinology 2015; 156:923-33. [PMID: 25549046 DOI: 10.1210/en.2014-1689] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Accumulation of visceral fat is associated with metabolic risk whereas excessive amounts of peripheral fat are considered less problematic. At the same time, altered white adipocyte mitochondrial bioenergetics has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. We therefore investigated whether the metabolic risk of visceral vs peripheral fat coincides with a difference in mitochondrial capacity of white adipocytes. We assessed bioenergetic parameters of subcutaneous inguinal and visceral epididymal white adipocytes from male C57BL/6N mice employing a comprehensive respirometry setup of intact and permeabilized adipocytes as well as isolated mitochondria. Inguinal adipocytes clearly featured a higher respiratory capacity attributable to increased mitochondrial respiratory chain content compared with epididymal adipocytes. The lower capacity of mitochondria from epididymal adipocytes was accompanied by an increased generation of reactive oxygen species per oxygen consumed. Feeding a high-fat diet (HFD) for 1 week reduced white adipocyte mitochondrial capacity, with stronger effects in epididymal when compared with inguinal adipocytes. This was accompanied by impaired body glucose homeostasis. Therefore, the limited bioenergetic performance combined with the proportionally higher generation of reactive oxygen species of visceral adipocytes could be seen as a candidate mechanism mediating the elevated metabolic risk associated with this fat depot.
Collapse
Affiliation(s)
- Theresa Schöttl
- Molecular Nutritional Medicine, Technische Universität München, Else Kröner Fresenius Center for Nutritional Medicine, 85350 Freising, Germany
| | | | | | | | | |
Collapse
|
|
27
|
Hilton C, Karpe F, Pinnick KE. Role of developmental transcription factors in white, brown and beige adipose tissues. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:686-96. [PMID: 25668679 DOI: 10.1016/j.bbalip.2015.02.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/08/2015] [Accepted: 02/03/2015] [Indexed: 02/06/2023]
Abstract
In this review we discuss the role of developmental transcription factors in adipose tissue biology with a focus on how these developmental genes may contribute to regional variation in adipose tissue distribution and function. Regional, depot-specific, differences in lipid handling and signalling (lipolysis, lipid storage and adipokine/lipokine signalling) are important determinants of metabolic health. At a cellular level, preadipocytes removed from their original depot and cultured in vitro retain depot-specific functional properties, implying that these are intrinsic to the cells and not a function of their environment in situ. High throughput screening has identified a number of developmental transcription factors involved in embryological development, including members of the Homeobox and T-Box gene families, that are strongly differentially expressed between regional white adipose tissue depots and also between brown and white adipose tissue. However, the significance of depot-specific developmental signatures remains unclear. Developmental transcription factors determine body patterning during embryogenesis. The divergent developmental origins of regional adipose tissue depots may explain their differing functional characteristics. There is evidence from human genetics that developmental genes determine adipose tissue distribution: in GWAS studies a number of developmental genes have been identified as being correlated with anthropometric measures of adiposity and fat distribution. Additionally, compelling functional studies have recently implicated developmental genes in both white adipogenesis and the so-called 'browning' of white adipose tissue. Understanding the genetic and developmental pathways in adipose tissue may help uncover novel ways to intervene with the function of adipose tissue in order to promote health.
Collapse
Affiliation(s)
- Catriona Hilton
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, OUH Trust, Churchill Hospital, Oxford, UK
| | - Katherine E Pinnick
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
| |
Collapse
|
|
28
|
Lu Q, Li M, Zou Y, Cao T. Induction of adipocyte hyperplasia in subcutaneous fat depot alleviated type 2 diabetes symptoms in obese mice. Obesity (Silver Spring) 2014; 22:1623-31. [PMID: 24435986 DOI: 10.1002/oby.20705] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Accepted: 01/13/2014] [Indexed: 01/14/2023]
Abstract
OBJECTIVE The role of subcutaneous adipose tissue (SAT) in the pathogenesis of type 2 diabetes is still under controversy. In this study, the metabolic effects of inducing adipocyte hyperplasia in SAT depots in obese mice were investigated. METHODS High fat diet was used to induce obesity and type 2 diabetes symptoms in C57BL6/J mice. To induce SAT expansion through hyperplasia, acellular adipogenic cocktails were injected around the SAT depots in high fat diet-induced obese mice. RESULTS Ten weeks after injections, significant neoadipogenesis was induced, which not only obviously expanded the volume of SATs but also significantly increased the adipocyte density within the whole SAT depots. Importantly, these mice exhibited improved glucose tolerance and insulin sensitivity (homeostatic model assessment) when compared to control group. Further studies suggested that these beneficial metabolic effects were associated with elevation of serum high-molecular-weight adiponectin level and reduction of ectopic lipid accumulation in liver. CONCLUSIONS These findings not only further supported the protective role of SAT in the pathogenesis of type 2 diabetes but also highlighted the importance of adipocyte hyperplasia in this protective effect.
Collapse
Affiliation(s)
- Qiqi Lu
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore; Faculty of Dentistry NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore
| | | | | | | |
Collapse
|
|
29
|
Kuo MMC, Kim S, Tseng CY, Jeon YH, Choe S, Lee DK. BMP-9 as a potent brown adipogenic inducer with anti-obesity capacity. Biomaterials 2014; 35:3172-9. [DOI: 10.1016/j.biomaterials.2013.12.063] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Accepted: 12/20/2013] [Indexed: 01/28/2023]
|
|
30
|
Hocking S, Samocha-Bonet D, Milner KL, Greenfield JR, Chisholm DJ. Adiposity and insulin resistance in humans: the role of the different tissue and cellular lipid depots. Endocr Rev 2013; 34:463-500. [PMID: 23550081 DOI: 10.1210/er.2012-1041] [Citation(s) in RCA: 193] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the "culprits" were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount. Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties. Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance. There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, irisin, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear. Further understanding of specific roles of different lipid depots may help new approaches to control obesity and its metabolic sequelae.
Collapse
Affiliation(s)
- Samantha Hocking
- Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Sydney, Australia.
| | | | | | | | | |
Collapse
|
|
31
|
Foster MT, Softic S, Caldwell J, Kohli R, de Kloet AD, Seeley RJ. Subcutaneous Adipose Tissue Transplantation in Diet-Induced Obese Mice Attenuates Metabolic Dysregulation While Removal Exacerbates It. Physiol Rep 2013; 1. [PMID: 23914298 PMCID: PMC3728904 DOI: 10.1002/phy2.15] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Adipose tissue distribution is an important determinant of obesity-related comorbidities. It is well established that central obesity (visceral adipose tissue accumulation) is a risk factor for many adverse health consequences such as dyslipidemia, insulin resistance, and type-2-diabetes. We hypothesize that the metabolic dysregulation that occurs following high fat diet-induced increases in adiposity are due to alterations in visceral adipose tissue function which influence lipid flux to the liver via the portal vein. This metabolic pathology is not exclusively due to increases in visceral adipose tissue mass but also driven by intrinsic characteristics of this particular depot. In Experiment 1, high fat diet (HFD)-induced obese control (abdominal incision, but no fat manipulation) or autologous (excision and subsequent relocation of adipose tissue) subcutaneous tissue transplantation to the visceral cavity. In Experiment 2, mice received control surgery, subcutaneous fat removal, or heterotransplantation (tissue from obese donor) to the visceral cavity. Body composition analysis and glucose tolerance tests were performed 4 weeks postsurgery. Adipose mass and portal adipokines, cytokines, lipids, and insulin were measured from samples collected at 5 weeks postsurgery. Auto- and heterotransplantation in obese mice improved glucose tolerance, decreased systemic insulin concentration, and reduced portal lipids and hepatic triglycerides compared with HFD controls. Heterotransplantation of subcutaneous adipose tissue to the visceral cavity in obese mice restored hepatic insulin sensitivity and reduced insulin and leptin concentrations to chow control levels. Fat removal, however, as an independent procedure exacerbated obesity-induced increases in leptin and insulin concentrations. Overall subcutaneous adipose tissue protects against aspects of metabolic dysregulation in obese mice. Transplantation-induced improvements do not occur via enhanced storage of lipid in adipose tissue, however, altered hepatic lipid regulation may play a contributory role.
Collapse
Affiliation(s)
- M T Foster
- Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, OH
| | | | | | | | | | | |
Collapse
|
|
32
|
Abstract
Visceral and s.c. fat exhibit different intrinsic properties, including rates of lipolysis, and are associated with differential risk for the development of type 2 diabetes. These effects are in part related to cell autonomous differences in gene expression. In the present study, we show that expression of Shox2 (Short stature homeobox 2) is higher in s.c. than visceral fat in both rodents and humans and that levels are further increased in humans with visceral obesity. Fat-specific disruption of Shox2 in male mice results in protection from high fat diet-induced obesity, with a preferential loss of s.c. fat. The reduced adipocyte size is secondary to a twofold increase in the expression of β3 adrenergic receptor (Adrb3) at both the mRNA and protein level and a parallel increase in lipolytic rate. These effects are mimicked by knockdown of Shox2 in C3H10T1/2 cells. Conversely, overexpression of Shox2 leads to a repression of Adrb3 expression and decrease lipolytic rate. Shox2 does not affect differentiation but directly interacts with CCAAT/enhancer binding protein alpha and attenuates its transcriptional activity of the Adrb3 promoter. Thus, Shox2 can regulate the expression of Adrb3 and control the rate of lipolysis and, in this way, exerts control of the phenotypic differences between visceral and s.c. adipocytes.
Collapse
|
|
33
|
Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Aspects Med 2012; 34:1-11. [PMID: 23068073 DOI: 10.1016/j.mam.2012.10.001] [Citation(s) in RCA: 581] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Obesity, defined as excess fat mass, increases risks for multiple metabolic diseases, such as type 2 diabetes, cardiovascular disease and several types of cancer. Over and above fat mass per se, the pattern of fat distribution, android or truncal as compared to gynoid or peripheral, has a profound influence on systemic metabolism and hence risk for metabolic diseases. Increases in upper body adipose tissue (visceral and abdominal subcutaneous) confer an independent risk, while the quantity of gluteofemoral adipose tissue is protective. Variations in the capacity of different depots to store and release fatty acids and to produce adipokines are important determinants of fat distribution and its metabolic consequences. Depot differences in cellular composition and physiology, including innervation and blood flow, likely influence their phenotypic properties. A number of lines of evidence also support the idea that adipocytes from different anatomical depots are intrinsically different as a result of genetic or developmental events. In this chapter, we will review the phenotypic characteristics of different adipose depots and mechanisms that link their depot-specific biology to metabolic complications in men and women.
Collapse
|
|
34
|
Foster MT, Pagliassotti MJ. Metabolic alterations following visceral fat removal and expansion: Beyond anatomic location. Adipocyte 2012; 1:192-199. [PMID: 23700533 PMCID: PMC3609102 DOI: 10.4161/adip.21756] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Increased visceral adiposity is a risk factor for metabolic disorders such as dyslipidemia, hypertension, insulin resistance and type 2 diabetes, whereas peripheral (subcutaneous) obesity is not. Though the specific mechanisms which contribute to these adipose depot differences are unknown, visceral fat accumulation is proposed to result in metabolic dysregulation because of increased effluent, e.g., fatty acids and/or adipokines/cytokines, to the liver via the hepatic portal vein. Pathological significance of visceral fat accumulation is also attributed to adipose depot/adipocyte-specific characteristics, specifically differences in structural, physiologic and metabolic characteristics compared with subcutaneous fat. Fat manipulations, such as removal or transplantation, have been utilized to identify location dependent or independent factors that play a role in metabolic dysregulation. Obesity-induced alterations in adipose tissue function/intrinsic characteristics, but not mass, appear to be responsible for obesity-induced metabolic dysregulation, thus “quality” is more important than “quantity.” This review summarizes the implications of obesity-induced metabolic dysfunction as it relates to anatomic site and inherent adipocyte characteristics.
Collapse
|
|
35
|
Baglioni S, Cantini G, Poli G, Francalanci M, Squecco R, Di Franco A, Borgogni E, Frontera S, Nesi G, Liotta F, Lucchese M, Perigli G, Francini F, Forti G, Serio M, Luconi M. Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS One 2012; 7:e36569. [PMID: 22574183 PMCID: PMC3344924 DOI: 10.1371/journal.pone.0036569] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 04/10/2012] [Indexed: 12/18/2022] Open
Abstract
Metabolic pathologies mainly originate from adipose tissue (AT) dysfunctions. AT differences are associated with fat-depot anatomic distribution in subcutaneous (SAT) and visceral omental (VAT) pads. We address the question whether the functional differences between the two compartments may be present early in the adipose stem cell (ASC) instead of being restricted to the mature adipocytes. Using a specific human ASC model, we evaluated proliferation/differentiation of ASC from abdominal SAT-(S-ASC) and VAT-(V-ASC) paired biopsies in parallel as well as the electrophysiological properties and functional activity of ASC and their in vitro-derived adipocytes. A dramatic difference in proliferation and adipogenic potential was observed between the two ASC populations, S-ASC having a growth rate and adipogenic potential significantly higher than V-ASC and giving rise to more functional and better organized adipocytes. To our knowledge, this is the first comprehensive electrophysiological analysis of ASC and derived-adipocytes, showing electrophysiological properties, such as membrane potential, capacitance and K(+)-current parameters which confirm the better functionality of S-ASC and their derived adipocytes. We document the greater ability of S-ASC-derived adipocytes to secrete adiponectin and their reduced susceptibility to lipolysis. These features may account for the metabolic differences observed between the SAT and VAT. Our findings suggest that VAT and SAT functional differences originate at the level of the adult ASC which maintains a memory of its fat pad of origin. Such stem cell differences may account for differential adipose depot susceptibility to the development of metabolic dysfunction and may represent a suitable target for specific therapeutic approaches.
Collapse
Affiliation(s)
- Silvana Baglioni
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Giulia Cantini
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Giada Poli
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Michela Francalanci
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Roberta Squecco
- Department of Physiological Sciences, University of Florence, Florence, Italy
| | - Alessandra Di Franco
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Elisa Borgogni
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Salvatore Frontera
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Gabriella Nesi
- Department of Human Pathology and Oncology, University of Florence, Florence, Italy
| | - Francesco Liotta
- Department of Internal Medicine, University of Florence, Florence, Italy
| | | | - Giuliano Perigli
- Department of General Surgery, University of Florence, Florence, Italy
| | - Fabio Francini
- Department of Physiological Sciences, University of Florence, Florence, Italy
| | - Gianni Forti
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Mario Serio
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - Michaela Luconi
- Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
- * E-mail:
| |
Collapse
|
|
36
|
Abstract
BACKGROUND: A low-grade state of adipose tissue inflammation associated with obesity has been linked to mechanisms of systemic metabolic dysfunction. However, the relation of clinical phenotypes to depot-specific inflammation has not been well examined in human obesity. OBJECTIVE: To characterize the inflammatory status of subcutaneous and visceral fat depots, as assessed by tissue presence of macrophage crown-like structures (CLS) as a hallmark of chronic inflammation, and determine the relation of systemic insulin resistance to inflammatory abnormalities in subcutaneous and visceral fat. METHODS: We collected adipose tissue simultaneously from subcutaneous and visceral (omental and mesenteric) depots in 92 obese participants (age 42±11 years; BMI⩾30 kg m−2) during planned bariatric surgery. Using immunohistochemistry, we categorized individuals as CLS+ or CLS− based on the presence or absence, respectively, of macrophage CLS in subcutaneous (CLSs), omental (CLSo) and mesenteric (CLSm) adipose depots. RESULTS: The majority of participants exhibited adipose tissue inflammation manifest by the presence of CLS (CLS+) in both subcutaneous and intra-abdominal visceral depots. CLS status in subcutaneous fat was highly sensitive and modestly specific for inflammation of visceral fat. In multivariable models, plasma insulin and homeostatis model assessment levels were positively associated with CLS+ status in all depots independent of age, waist circumference, BMI and type 2 diabetes, and worsened with the increasing number of adipose regions involved. CONCLUSIONS: In severely obese participants, systemic insulin resistance is linked to adipose inflammation in both subcutaneous and visceral depots. The findings suggest that examination of subcutaneous regions that are more easily accessible by transcutaneous biopsy may prove useful in clinical studies designed to investigate adipose phenotypes in relation to human disease.
Collapse
|
|
37
|
Foster MT, Shi H, Softic S, Kohli R, Seeley RJ, Woods SC. Transplantation of non-visceral fat to the visceral cavity improves glucose tolerance in mice: investigation of hepatic lipids and insulin sensitivity. Diabetologia 2011; 54:2890-9. [PMID: 21805228 PMCID: PMC5451325 DOI: 10.1007/s00125-011-2259-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Accepted: 06/29/2011] [Indexed: 01/29/2023]
Abstract
AIMS/HYPOTHESIS Intra-abdominal transplantation of non-visceral adipose tissue in rodents, simulating increased abdominal fat in obesity, paradoxically improves glucose tolerance and insulin sensitivity. We hypothesised that this improvement is due to transplant-induced enhanced uptake of fatty acids by adipose tissue, thus reducing fatty acid flux into, and triacylglycerol storage in, the liver. METHODS In Experiment 1, mice were sham-operated or received heterologous epididymal white adipose tissue (WAT; EWAT) or visceral WAT (VWAT) transplantation to the portal and splanchnic circulation regions in the visceral cavity. In Experiment 2, inguinal WAT (IWAT) or EWAT was removed and subsequently transplanted to the visceral cavity of the same mouse (autotransplant). IWAT and EWAT autotransplants were repeated in Experiment 3 and compared with heterotransplants. RESULTS Heterotransplantation of VWAT did not alter glucose tolerance, whereas auto- or hetero-transplantation of EWAT or IWAT significantly improved glucose tolerance. Transplantation-induced improvements in glucose tolerance 4 weeks after surgery coincided with decreased liver triacylglycerol, decreased portal plasma lipids and increased hepatic insulin sensitivity. By 8 weeks, these changes were apparent only in mice with autotransplantation. Heterologous EWAT transplantation-induced glucose improvement persisted without altered liver metabolism. CONCLUSIONS/INTERPRETATION Increases in visceral fat, via transplantation of visceral or non-visceral adipose tissue, is not a major risk factor for glucose intolerance. In fact, there are dynamic metabolic improvements following transplantation that include decreased portal lipids and improved liver metabolism, but these improvements are transient under certain circumstances.
Collapse
MESH Headings
- Adipose Tissue, White/metabolism
- Adipose Tissue, White/pathology
- Adipose Tissue, White/transplantation
- Animals
- Disease Models, Animal
- Epididymis
- Glucose Intolerance/etiology
- Glucose Intolerance/prevention & control
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Insulin Resistance
- Intra-Abdominal Fat/metabolism
- Intra-Abdominal Fat/pathology
- Intra-Abdominal Fat/transplantation
- Lipid Metabolism
- Lipids/blood
- Liver/metabolism
- Liver/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Obesity, Abdominal/blood
- Obesity, Abdominal/metabolism
- Obesity, Abdominal/pathology
- Obesity, Abdominal/physiopathology
- Peritoneum/surgery
- Recombinant Proteins/metabolism
- Transplantation, Autologous
- Transplantation, Homologous
Collapse
Affiliation(s)
- M T Foster
- Obesity Research Center, Department of Psychiatry, University of Cincinnati, 2170 E. Galbraith Road, Cincinnati, OH 45237, USA.
| | | | | | | | | | | |
Collapse
|
|
38
|
Foster MT, Shi H, Seeley RJ, Woods SC. Removal of intra-abdominal visceral adipose tissue improves glucose tolerance in rats: role of hepatic triglyceride storage. Physiol Behav 2011; 104:845-54. [PMID: 21683727 PMCID: PMC3183256 DOI: 10.1016/j.physbeh.2011.04.064] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Revised: 03/29/2011] [Accepted: 04/10/2011] [Indexed: 11/21/2022]
Abstract
Epidemiological studies have demonstrated a strong link between increased visceral fat and metabolic syndrome. In rodents, removal of intra-abdominal but non-visceral fat improves insulin sensitivity and glucose homeostasis, though previous studies make an imprecise comparison to human physiology because actual visceral fat was not removed. We hypothesize that nutrient release from visceral adipose tissue may have greater consequences on metabolic regulation than nutrient release from non-visceral adipose depots since the latter drains into systemic but not portal circulation. To assess this we surgically decreased visceral white adipose tissue (~0.5 g VWATx) and compared the effects to removal of non-visceral epididymal fat (~4 g; EWATx), combination removal of visceral and non-visceral fat (~4.5 g; EWATx/VWATx) and sham-operated controls, in chow-fed rats. At 8 weeks after surgery, only the groups with visceral fat removed had a significantly improved glucose tolerance, although 8 times more fat was removed in EWATx compared with VWATx. This suggests that mechanisms controlling glucose metabolism are relatively more sensitive to reductions in visceral adipose tissue mass. Groups with visceral fat removed also had significantly decreased hepatic lipoprotein lipase (LPL) and triglyceride content compared with controls, while carnitine palmitoyltransferase (CPT-1A) was decreased in all fat-removal groups. In a preliminary experiment, we assessed the opposite hypothesis; i.e., we transplanted excess visceral fat from a donor rat to the visceral cavity (omentum and mesentery), which drains into the hepatic portal vein, of a recipient rat but observed no major metabolic effect. Overall, our results indicate surgical removal of intra-abdominal fat improves glucose tolerance through mechanism that may be mediated by reductions in liver triglyceride.
Collapse
Affiliation(s)
- Michelle T Foster
- Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, OH 45237, United States.
| | | | | | | |
Collapse
|
|
39
|
Targeting thermogenesis and related pathways in anti-obesity drug discovery. Pharmacol Ther 2011; 131:295-308. [PMID: 21514319 DOI: 10.1016/j.pharmthera.2011.04.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2011] [Accepted: 03/29/2011] [Indexed: 01/12/2023]
Abstract
The health consequences of the obesity epidemic are a huge burden on patients and society. Yet it remains an unmet therapeutic need. Lifestyle or behaviour modification, although desirable, seems to benefit only a few and bariatric surgery is not an option for all and not without risks. Nevertheless, bariatric surgery is currently the gold standard in terms of weight loss therapy and any weight loss agent will be in combination with management of lifestyle modification. Sadly, there is a poor history for the pharmacological treatment of obesity and repeated safety concerns have attracted intense regulatory scrutiny. Indeed, recent market withdrawals leave us with just one agent approved for the long term treatment of obesity and that is only mildly efficacious in terms of weight loss, although it is beneficial in terms of metabolic health. There are two broad pharmacological approaches that can be applied in obesity drug discovery: reduce intake (or absorption) or increase expenditure (thermogenesis) of calories. In this review we will look at the latter approach. We will cover regulatory requirements and the rationale for this approach. We believe that post-obese subjects display abnormal metabolic responses to weight loss that almost inevitably leads to weight regain. We will then explore a number of approaches that potentially increase thermogenesis in humans. The challenge we have is in accumulating enough human data to validate this approach using drugs.
Collapse
|
|
40
|
Marino M, Masella R, Bulzomi P, Campesi I, Malorni W, Franconi F. Nutrition and human health from a sex-gender perspective. Mol Aspects Med 2011; 32:1-70. [PMID: 21356234 DOI: 10.1016/j.mam.2011.02.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 01/25/2011] [Accepted: 02/18/2011] [Indexed: 02/07/2023]
Abstract
Nutrition exerts a life-long impact on human health, and the interaction between nutrition and health has been known for centuries. The recent literature has suggested that nutrition could differently influence the health of male and female individuals. Until the last decade of the 20th century, research on women has been neglected, and the results obtained in men have been directly translated to women in both the medicine and nutrition fields. Consequently, most modern guidelines are based on studies predominantly conducted on men. However, there are many sex-gender differences that are the result of multifactorial inputs, including gene repertoires, sex steroid hormones, and environmental factors (e.g., food components). The effects of these different inputs in male and female physiology will be different in different periods of ontogenetic development as well as during pregnancy and the ovarian cycle in females, which are also age dependent. As a result, different strategies have evolved to maintain male and female body homeostasis, which, in turn, implies that there are important differences in the bioavailability, metabolism, distribution, and elimination of foods and beverages in males and females. This article will review some of these differences underlying the impact of food components on the risk of developing diseases from a sex-gender perspective.
Collapse
Affiliation(s)
- Maria Marino
- Department of Biology, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | | | | | | | | | | |
Collapse
|
|
41
|
Abstract
OBJECTIVE The "portal hypothesis" proposes that the liver is directly exposed to free fatty acids and cytokines increasingly released from visceral fat tissue into the portal vein of obese subjects, thus rendering visceral fat accumulation particularly hazardous for the development of hepatic insulin resistance and type 2 diabetes. In the present study, we used a fat transplantation paradigm to (artificially) increase intra-abdominal fat mass to test the hypothesis that venous drainage of fat tissue determines its impact on glucose homeostasis. RESEARCH DESIGN AND METHODS Epididymal fat pads of C57Bl6/J donor mice were transplanted into littermates, either to the parietal peritoneum (caval/systemic venous drainage) or, by using a novel approach, to the mesenterium, which confers portal venous drainage. RESULTS Only mice receiving the portal drained fat transplant developed impaired glucose tolerance and hepatic insulin resistance. mRNA expression of proinflammatory cytokines was increased in both portally and systemically transplanted fat pads. However, portal vein (but not systemic) plasma levels of interleukin (IL)-6 were elevated only in mice receiving a portal fat transplant. Intriguingly, mice receiving portal drained transplants from IL-6 knockout mice showed normal glucose tolerance. CONCLUSIONS These results demonstrate that the metabolic fate of intra-abdominal fat tissue transplantation is determined by the delivery of inflammatory cytokines to the liver specifically via the portal system, providing direct evidence in support of the portal hypothesis.
Collapse
Affiliation(s)
- Julia M. Rytka
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Eugen J. Schoenle
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Corresponding author: Daniel Konrad,
| |
Collapse
|
|
42
|
Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011; 121:96-105. [PMID: 21123942 PMCID: PMC3007155 DOI: 10.1172/jci44271] [Citation(s) in RCA: 1007] [Impact Index Per Article: 71.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Accepted: 10/13/2010] [Indexed: 12/20/2022] Open
Abstract
The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat-like gene program and thermogenesis in subcutaneous adipose tissues.
Collapse
Affiliation(s)
- Patrick Seale
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Heather M. Conroe
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Jennifer Estall
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Shingo Kajimura
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Andrea Frontini
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Jeff Ishibashi
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Paul Cohen
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Saverio Cinti
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Bruce M. Spiegelman
- Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular Pathology and Innovative Therapies, School of Medicine, University of Ancona (Politecnica delle Marche), Ancona, Italy
| |
Collapse
|
|
43
|
Abstract
Exercise, together with a low-energy diet, is the first-line treatment for type 2 diabetes type 2 diabetes . Exercise improves insulin sensitivity insulin sensitivity by increasing the number or function of muscle mitochondria mitochondria and the capacity for aerobic metabolism, all of which are low in many insulin-resistant subjects. Cannabinoid 1-receptor antagonists and β-adrenoceptor agonists improve insulin sensitivity in humans and promote fat oxidation in rodents independently of reduced food intake. Current drugs for the treatment of diabetes are not, however, noted for their ability to increase fat oxidation, although the thiazolidinediones increase the capacity for fat oxidation in skeletal muscle, whilst paradoxically increasing weight gain.There are a number of targets for anti-diabetic drugs that may improve insulin sensitivity insulin sensitivity by increasing the capacity for fat oxidation. Their mechanisms of action are linked, notably through AMP-activated protein kinase, adiponectin, and the sympathetic nervous system. If ligands for these targets have obvious acute thermogenic activity, it is often because they increase sympathetic activity. This promotes fuel mobilisation, as well as fuel oxidation. When thermogenesis thermogenesis is not obvious, researchers often argue that it has occurred by using the inappropriate device of treating animals for days or weeks until there is weight (mainly fat) loss and then expressing energy expenditure energy expenditure relative to body weight. In reality, thermogenesis may have occurred, but it is too small to detect, and this device distracts us from really appreciating why insulin sensitivity has improved. This is that by increasing fatty acid oxidation fatty acid oxidation more than fatty acid supply, drugs lower the concentrations of fatty acid metabolites that cause insulin resistance. Insulin sensitivity improves long before any anti-obesity effect can be detected.
Collapse
Affiliation(s)
- Jonathan R S Arch
- Clore Laboratory, University of Buckingham, Buckingham, MK18 1EG, UK
| |
Collapse
|
|
44
|
Zhang L, Riepler SJ, Turner N, Enriquez RF, Lee ICJ, Baldock PA, Herzog H, Sainsbury A. Y2 and Y4 receptor signaling synergistically act on energy expenditure and physical activity. Am J Physiol Regul Integr Comp Physiol 2010; 299:R1618-28. [DOI: 10.1152/ajpregu.00345.2010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Neuropeptide Y receptors are critical regulators of energy homeostasis and are well known for their powerful influence on feeding, but their roles in other important aspects of energy homeostasis, such as energy expenditure and their functional interactions in these processes, are largely unknown. Here we show that mice lacking both Y2 and Y4 receptors exhibited a reduction in adiposity, more prominent in intra-abdominal vs. subcutaneous fat, and an increase in lean mass as determined by dual-energy X-ray absorptiometry. These changes were more pronounced than those seen in mice with Y2 or Y4 receptor single deletion, demonstrating the important roles and synergy of Y2 and Y4 signaling in the regulation of body composition. These changes in body composition occurred without significant changes in food intake, but energy expenditure and physical activity were significantly increased in Y4−/− and particularly in Y2−/−Y4−/− but not in Y2−/− mice, suggesting a critical role of Y4 signaling and synergistic interactions with Y2 signaling in the regulation of energy expenditure and physical activity. Y2−/− and Y4−/− mice also exhibited a decrease in respiratory exchange ratio with no further synergistic decrease in Y2−/−Y4−/− mice, suggesting that Y2 and Y4 signaling each play important and independent roles in the regulation of substrate utilization. The synergy between Y2 and Y4 signaling in regulating fat mass may be related to differences in mitochondrial oxidative capacity, since Y2−/−Y4−/− but not Y2−/− or Y4−/− mice showed significant increases in muscle protein levels of peroxisome proliferator-activated receptor (PPAR)γ coactivator (PGC)-1α, and mitochondrial respiratory chain complexes I and III. Taken together, this work demonstrates the critical roles of Y2 and Y4 receptors in the regulation of body composition and energy metabolism, highlighting dual antagonism of Y2 and Y4 receptors as a potentially effective anti-obesity treatment.
Collapse
Affiliation(s)
| | | | - Nigel Turner
- Diabetes and Obesity Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney, Australia
- St. Vincent's Hospital Clinical School,
| | | | | | | | - Herbert Herzog
- Neuroscience Research Program and
- Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Amanda Sainsbury
- Neuroscience Research Program and
- School of Medical Sciences, and
| |
Collapse
|
|
45
|
Foster MT, Shi H, Seeley RJ, Woods SC. Transplantation or removal of intra-abdominal adipose tissue prevents age-induced glucose insensitivity. Physiol Behav 2010; 101:282-8. [PMID: 20570685 PMCID: PMC2910801 DOI: 10.1016/j.physbeh.2010.05.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2009] [Revised: 05/10/2010] [Accepted: 05/20/2010] [Indexed: 12/15/2022]
Abstract
Increases in intra-abdominal fat, a common feature associated with aging, is an established risk factor for insulin resistance, diabetes and the metabolic syndrome. To examine the direct contribution of intra-abdominal fat in the pathophysiology of insulin resistance we altered fat volume via removal or transplantation in a naturally occurring age-induced moderate model of obesity and insulin resistance. This was accomplished by bilateral removal of epididymal white adipose tissue (Lipx) or transplantation of donor fat into the intra-abdominal side of the peritoneal cavity of 28-week old rats. Control animals received sham surgery. Glucose tolerance was evaluated at baseline and 4 and 8weeks post-surgery in all groups, and fasting insulin and leptin were additionally measured in 28-week old rats. In addition, fasted and fed triglyceride, cholesterol and fatty acid concentrations were measured. Before surgery 28-week old rats weighed more and were glucose intolerant compared with 8-week old controls. Both Lipx and transplantation significantly prevented age-induced decreases in glucose tolerance, with Lipx causing improvement at 4weeks which declined by 8weeks; and with a significant transplantation improvement at 8weeks only. Lipx significantly increased insulin secretion 15min after a bolus injection of 0.75mg/kg dextrose at 4 and 8weeks compared with controls, while transplantation caused a significant ( approximately 220%) increase in fasted leptin level at 4weeks only. Taken together, these data suggest that surgical removal or addition of intra-abdominal fat prevents age-induced insulin resistance by different mechanisms and is a suitable model to investigate naturally occurring obesity.
Collapse
Affiliation(s)
- Michelle T Foster
- Obesity Research Center, Department of Psychiatry, University of Cincinnati, 2170 E. Galbraith Road, Cincinnati, OH 45237, United States.
| | | | | | | |
Collapse
|
|
46
|
Expression Profile in Omental and Subcutaneous Adipose Tissue from Lean and Obese Subjects. Repression of Lipolytic and Lipogenic Genes. Obes Surg 2010; 21:633-43. [DOI: 10.1007/s11695-010-0246-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
47
|
Zhang Y. Utility of transplantation in studying adipocyte biogenesis and function. Mol Cell Endocrinol 2010; 318:15-23. [PMID: 19733623 PMCID: PMC2826534 DOI: 10.1016/j.mce.2009.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Revised: 08/27/2009] [Accepted: 08/30/2009] [Indexed: 10/20/2022]
Abstract
Adipose tissue plays important roles in the regulation of energy homeostasis and metabolism. Two features distinguish adipose tissue from other organs--the ability to greatly expand its mass, via increases in cell size and/or number, and the wide anatomical distribution. While adipose tissue function is greatly affected by adipocyte size and anatomic location, regulations of adipocyte size, number, and body fat distribution are poorly understood. Transplantation of either mature adipose tissue or adipocyte progenitor cells has been used in studying adipocyte function and biogenesis. In this review, we will attempt to summarize methodological considerations for transplantation, including selections of donor material, transplantation site and the length of transplantation study, as well as effects of these factors and vascularization and innervation on the function of transplants. Specific studies are also reviewed to illustrate the utility of adipose tissue transplants in studying adipose tissue function and biogenesis. The focus is on studies in three areas: (1) use of transplants in demonstrating adipose tissue function, such as effects of adipose tissue transplants on metabolism and energy homeostasis of the recipient animals and depot-specific differences in adipose tissue function; (2) use of transplantation to dissect direct or cell-autonomous from indirect or non-cell-autonomous effects of leptin signaling and sex on adipocyte size; (3) use of transplantation in the identification of adipocyte progenitor cells and lineage analysis. Finally, future applications of transplantation in studying depot-specific adipocyte biogenesis, and genetic and hormonal effects of sex and age on adipocyte biogenesis and function are discussed.
Collapse
Affiliation(s)
- Yiying Zhang
- Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY 10032, USA.
| |
Collapse
|
|
48
|
Abstract
Humans and other mammals have three main adipose tissue depots: visceral white adipose tissue, subcutaneous white adipose tissue and brown adipose tissue, each of which possesses unique cell-autonomous properties. In contrast to visceral adipose tissue, which can induce detrimental metabolic effects, subcutaneous white adipose tissue and brown adipose tissue have the potential to benefit metabolism by improving glucose homeostasis and increasing energy consumption. In addition, adipose tissue contains adipose-derived stem cells, which possess the ability to differentiate into multiple lineages, a property that might be of value for the repair or replacement of various damaged cell types. Adipose tissue transplantation has primarily been used as a tool to study physiology and for human reconstructive surgery. Transplantation of adipose tissue is, however, now being explored as a possible tool to promote the beneficial metabolic effects of subcutaneous white adipose tissue and brown adipose tissue, as well as adipose-derived stem cells. Ultimately, the clinical applicability of adipose tissue transplantation for the treatment of obesity and metabolic disorders will reside in the achievable level of safety, reliability and efficacy compared with other treatments.
Collapse
Affiliation(s)
- Thien T Tran
- Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
| | | |
Collapse
|
|
49
|
Abstract
The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics.
Collapse
Affiliation(s)
- Eleonore Maury
- Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, Illinois 60208
- Department of Neurobiology and Physiology, Northwestern University, 2200 Campus Drive, Evanston, Illinois 60208
| | - Kathryn Moynihan Ramsey
- Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, Illinois 60208
- Department of Neurobiology and Physiology, Northwestern University, 2200 Campus Drive, Evanston, Illinois 60208
| | - Joseph Bass
- Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, Illinois 60208
- Department of Neurobiology and Physiology, Northwestern University, 2200 Campus Drive, Evanston, Illinois 60208
| |
Collapse
|
|
50
|
Zhang L, Macia L, Turner N, Enriquez RF, Riepler SJ, Nguyen AD, Lin S, Lee NJ, Shi YC, Yulyaningsih E, Slack K, Baldock PA, Herzog H, Sainsbury A. Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion. Int J Obes (Lond) 2009; 34:357-73. [PMID: 19918245 DOI: 10.1038/ijo.2009.232] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Neuropeptide Y and its Y receptors are important players in the regulation of energy homeostasis. However, while their functions in feeding regulation are well recognized, functions in other critical aspects of energy homeostasis are largely unknown. To investigate the function of Y1 receptors in the regulation of energy homeostasis, we examined energy expenditure, physical activity, body composition, oxidative fuel selection and mitochondrial oxidative capacity in germline Y1(-/-) mice as well as in a conditional Y1-receptor-knockdown model in which Y1 receptors were knocked down in peripheral tissues of adult mice. RESULTS Germline Y1(-/-) mice of both genders not only exhibit a decreased respiratory exchange ratio, indicative of increased lipid oxidation, but interestingly also develop late-onset obesity. However, the increased lipid oxidation is a primary effect of Y1 deletion rather than secondary to increased adiposity, as young Y1(-/-) mice are lean and show the same effect. The mechanism behind this is likely because of increased liver and muscle protein levels of carnitine palmitoyltransferase-1 (CPT-1) and maximal activity of key enzymes involved in beta-oxidation; beta-hydroxyacyl CoA dehydrogenase (betaHAD) and medium-chain acyl-CoA dehydrogenase (MCAD), leading to increased mitochondrial capacity for fatty acid transport and oxidation. These effects are controlled by peripheral Y1-receptor signalling, as adult-onset conditional Y1 knockdown in peripheral tissues also leads to increased lipid oxidation, liver CPT-1 levels and betaHAD activity. Importantly, these mice are resistant to diet-induced obesity. CONCLUSIONS This work shows the primary function of peripheral Y1 receptors in the regulation of oxidative fuel selection and adiposity, opening up new avenues for anti-obesity treatments by targeting energy utilization in peripheral tissues rather than suppressing appetite by central effects.
Collapse
Affiliation(s)
- L Zhang
- Neuroscience Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|