Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
Add more filters











Publication year range
2.
PLoS Biol ; 22(6): e3002641, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38833481

ABSTRACT

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.


Subject(s)
Diet, High-Fat , Fatty Acids , Hypothalamus , MicroRNAs , Obesity, Maternal , Animals , Female , Humans , Male , Mice , Pregnancy , Diet, High-Fat/adverse effects , Fatty Acids/metabolism , Hypothalamus/metabolism , Mice, Inbred C57BL , MicroRNAs/metabolism , MicroRNAs/genetics , Neurons/metabolism , Obesity/metabolism , Obesity/genetics , Obesity, Maternal/metabolism , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/genetics
3.
Med ; 5(9): 1083-1095.e6, 2024 Sep 13.
Article in English | MEDLINE | ID: mdl-38906141

ABSTRACT

BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them. FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.


Subject(s)
Energy Metabolism , Leptin , Obesity , Adult , Female , Humans , Male , Middle Aged , Adiponectin/genetics , Adiponectin/metabolism , Case-Control Studies , Energy Metabolism/genetics , Leptin/blood , Leptin/genetics , Leptin/metabolism , Loss of Function Mutation , Membrane Proteins/genetics , Obesity/genetics , Obesity/metabolism , Overweight/genetics , Thyroid Hormones/blood , Thyroid Hormones/metabolism
4.
J Endocrinol ; 262(1)2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38642584

ABSTRACT

Obesity and diabetes represent two increasing and invalidating public health issues that often coexist. It is acknowledged that fat mass excess predisposes to insulin resistance and type 2 diabetes mellitus (T2D), with the increasing incidence of the two diseases significantly associated. Moreover, emerging evidence suggests that obesity might also accelerate the appearance of type 1 diabetes (T1D), which is now a relatively frequent comorbidity in patients with obesity. It is a common clinical finding that not all patients with obesity will develop diabetes at the same level of adiposity, with gender, genetic, and ethnic factors playing an important role in defining the timing of diabetes appearance. The adipose tissue (AT) expandability hypothesis explains this paradigm, indicating that the individual capacity to appropriately store energy surplus in the form of fat within the AT determines and prevents the toxic deposition of lipids in other organs, such as the pancreas. Thus, we posit that when the maximal storing capacity of AT is exceeded, individuals will develop T2D. In this review, we provide insight into mechanisms by which the AT controls pancreas lipid content and homeostasis in case of obesity to offer an adipocentric perspective of pancreatic lipotoxicity in the pathogenesis of diabetes. Moreover, we suggest that improving AT function is a valid therapeutic approach to fighting obesity-associated complications including diabetes.


Subject(s)
Adipose Tissue , Diabetes Mellitus, Type 2 , Obesity , Pancreas , Humans , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/etiology , Obesity/metabolism , Adipose Tissue/metabolism , Adipose Tissue/pathology , Pancreas/metabolism , Pancreas/pathology , Lipid Metabolism , Diabetes Mellitus, Type 1/metabolism , Insulin Resistance/physiology , Animals
5.
EMBO J ; 43(11): 2127-2165, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38580776

ABSTRACT

The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often considered to be hyperoxic, but pericellular oxygen levels, which are affected by oxygen diffusivity and consumption, are rarely reported. Here, we provide evidence that several cell types in culture actually experience local hypoxia, with important implications for cell metabolism and function. We focused initially on adipocytes, as adipose tissue hypoxia is frequently observed in obesity and precedes diminished adipocyte function. Under standard conditions, cultured adipocytes are highly glycolytic and exhibit a transcriptional profile indicative of physiological hypoxia. Increasing pericellular oxygen diverted glucose flux toward mitochondria, lowered HIF1α activity, and resulted in widespread transcriptional rewiring. Functionally, adipocytes increased adipokine secretion and sensitivity to insulin and lipolytic stimuli, recapitulating a healthier adipocyte model. The functional benefits of increasing pericellular oxygen were also observed in macrophages, hPSC-derived hepatocytes and cardiac organoids. Our findings demonstrate that oxygen is limiting in many terminally-differentiated cell types, and that considering pericellular oxygen improves the quality, reproducibility and translatability of culture models.


Subject(s)
Adipocytes , Cell Differentiation , Oxygen , Oxygen/metabolism , Adipocytes/metabolism , Adipocytes/cytology , Humans , Cell Culture Techniques/methods , Animals , Glycolysis , Hepatocytes/metabolism , Cell Hypoxia , Mitochondria/metabolism , Mice , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Cells, Cultured , Glucose/metabolism , Macrophages/metabolism
6.
Mol Metab ; 65: 101589, 2022 11.
Article in English | MEDLINE | ID: mdl-36064109

ABSTRACT

OBJECTIVES: Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. METHODS: Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice. RESULTS: Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice. CONCLUSIONS: Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress.


Subject(s)
Fatty Liver , Insulin Resistance , Animals , Body Weight , Fatty Liver/genetics , Fatty Liver/metabolism , Fibroblast Growth Factors , Growth Differentiation Factor 15/genetics , Hormones , Humans , Insulin Resistance/genetics , Mice , Mice, Knockout , Obesity/genetics , Obesity/metabolism
7.
Clin Sci (Lond) ; 135(19): 2265-2283, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34643676

ABSTRACT

Heart failure with preserved ejection fraction (HFpEF) is a growing public health concern, with rising incidence alongside high morbidity and mortality. However, the pathophysiology of HFpEF is not yet fully understood. The association between HFpEF and the metabolic syndrome (MetS) suggests that dysregulated lipid metabolism could drive diastolic dysfunction and subsequent HFpEF. Herein we summarise recent advances regarding the pathogenesis of HFpEF in the context of MetS, with a focus on impaired lipid handling, myocardial lipid accumulation and subsequent lipotoxicity.


Subject(s)
Heart Failure/metabolism , Lipid Metabolism , Metabolic Syndrome/metabolism , Myocardium/metabolism , Stroke Volume , Ventricular Function, Left , Animals , Cardiometabolic Risk Factors , Heart Failure/epidemiology , Heart Failure/pathology , Heart Failure/physiopathology , Humans , Metabolic Syndrome/epidemiology , Metabolic Syndrome/pathology , Metabolic Syndrome/physiopathology , Myocardium/pathology , Prognosis , Risk Assessment , Signal Transduction
8.
Nat Metab ; 3(9): 1150-1162, 2021 09.
Article in English | MEDLINE | ID: mdl-34531575

ABSTRACT

Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune-tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the metabolic regulation of macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical T helper 2 cell cytokine interleukin-4 to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising reactive oxygen species levels. Reactive oxygen species serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.


Subject(s)
Antioxidants/metabolism , Fatty Acids/biosynthesis , Macrophages/metabolism , Sterol Regulatory Element Binding Protein 1/metabolism , Animals , Dexamethasone/pharmacology , Humans , Interleukin-4/pharmacology , Lipopolysaccharides/pharmacology , Macrophage Activation , Macrophages/drug effects , Mice , Mice, Knockout , Nippostrongylus/isolation & purification , Nippostrongylus/pathogenicity , RAW 264.7 Cells , Sequence Analysis, RNA/methods , Strongylida Infections/immunology , Strongylida Infections/parasitology , Up-Regulation
9.
Mol Metab ; 48: 101220, 2021 06.
Article in English | MEDLINE | ID: mdl-33774223

ABSTRACT

OBJECTIVE: Neuroimmune interactions between the sympathetic nervous system (SNS) and macrophages are required for the homeostasis of multiple tissues, including the adipose tissue. It has been proposed that the SNS maintains adipose tissue macrophages (ATMs) in an anti-inflammatory state via direct norepinephrine (NE) signaling to macrophages. This study aimed to investigate the physiological importance of this paradigm by utilizing a mouse model in which the adrenergic signaling from the SNS to macrophages, but not to other adipose tissue cells, was disrupted. METHODS: We generated a macrophage-specific B2AR knockout mouse (Adrb2ΔLyz2) by crossing Adrb2fl/fl and Lyz2Cre/+ mice. We have previously shown that macrophages isolated from Adrb2ΔLyz2 animals do not respond to NE stimulation in vitro. Herein we performed a metabolic phenotyping of Adrb2ΔLyz2 mice on either chow or high-fat diet (HFD). We also assessed the adipose tissue function of Adrb2ΔLyz2 animals during fasting and cold exposure. Finally, we transplanted Adrb2ΔLyz2 bone marrow to low-density lipoprotein receptor (LDLR) knockout mice and investigated the development of atherosclerosis during Western diet feeding. RESULTS: We demonstrated that SNS-associated ATMs have a transcriptional profile indicative of activated beta-2 adrenergic receptor (B2AR), the main adrenergic receptor isoform in myeloid cells. However, Adrb2ΔLyz2 mice have unaltered energy balance on a chow or HFD. Furthermore, Adrb2ΔLyz2 mice show similar levels of adipose tissue inflammation and function during feeding, fasting, or cold exposure, and develop insulin resistance during HFD at the same rate as controls. Finally, macrophage-specific B2AR deletion does not affect the development of atherosclerosis on an LDL receptor-null genetic background. CONCLUSIONS: Overall, our data suggest that the SNS does not directly modulate the phenotype of adipose tissue macrophages in either lean mice or mouse models of cardiometabolic disease. Instead, sympathetic nerve activity exerts an indirect effect on adipose tissue macrophages through the modulation of adipocyte function.


Subject(s)
Atherosclerosis/complications , Atherosclerosis/metabolism , Insulin Resistance/genetics , Macrophages/metabolism , Obesity/complications , Obesity/metabolism , Panniculitis/metabolism , Receptors, Adrenergic, beta-2/metabolism , Signal Transduction/genetics , Adipocytes/metabolism , Adipose Tissue, White/metabolism , Animals , Atherosclerosis/genetics , Bone Marrow Transplantation/methods , Cells, Cultured , Diet, High-Fat/adverse effects , Diet, Western/adverse effects , Disease Models, Animal , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/genetics , Panniculitis/genetics , Phenotype , Receptors, Adrenergic, beta-2/genetics , Sympathetic Nervous System/metabolism
10.
Mol Metab ; 48: 101210, 2021 06.
Article in English | MEDLINE | ID: mdl-33722690

ABSTRACT

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. METHODS AND RESULTS: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. CONCLUSIONS: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.


Subject(s)
Cholesterol/biosynthesis , Disease Progression , Intracellular Signaling Peptides and Proteins/metabolism , Lipogenesis/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Animals , Biomarkers/metabolism , Diet, Western , Female , Humans , Insulin Resistance/genetics , Intracellular Signaling Peptides and Proteins/genetics , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Non-alcoholic Fatty Liver Disease/genetics , Transcriptome
11.
FASEB J ; 35(2): e21266, 2021 02.
Article in English | MEDLINE | ID: mdl-33484195

ABSTRACT

Tissue-resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an anti-inflammatory and tissue-reparative phenotype in macrophages. As NE has a well-established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow-derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2-adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride-laden macrophages. We demonstrate that these responses are mediated by a B2AR activation-dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases.


Subject(s)
Adrenergic Agonists/pharmacology , Macrophages/metabolism , Norepinephrine/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Triglycerides/metabolism , Animals , Cells, Cultured , Diacylglycerol O-Acyltransferase/genetics , Diacylglycerol O-Acyltransferase/metabolism , Leukocytes/metabolism , Lipid Droplets/metabolism , Macrophages/drug effects , Male , Mice , Mice, Inbred C57BL , Myocardium/cytology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Transcriptome
12.
Cells ; 9(5)2020 05 12.
Article in English | MEDLINE | ID: mdl-32408587

ABSTRACT

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients' endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin-zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases.


Subject(s)
Cellular Senescence , Coronary Vessels/pathology , Endothelial Cells/pathology , Inflammation/pathology , Lamin Type A/metabolism , Oxidative Stress , Cell Nucleus/metabolism , Cell Nucleus Shape , Cells, Cultured , DNA Damage , Endothelial Cells/metabolism , Humans , Nitric Oxide Synthase/metabolism , Protein Prenylation
13.
Elife ; 82019 08 16.
Article in English | MEDLINE | ID: mdl-31418690

ABSTRACT

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs.


Subject(s)
Adipose Tissue/pathology , Inflammation/pathology , Macrophages/metabolism , Obesity/pathology , Phosphatidylcholines/metabolism , Animals , Choline-Phosphate Cytidylyltransferase/deficiency , Choline-Phosphate Cytidylyltransferase/metabolism , Disease Models, Animal , Gene Deletion , Humans , Insulin Resistance , Mice, Obese
14.
Sci Rep ; 9(1): 2903, 2019 02 27.
Article in English | MEDLINE | ID: mdl-30814564

ABSTRACT

Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that female mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.


Subject(s)
Hypothalamus/metabolism , Obesity/prevention & control , Protein Phosphatase 1/genetics , Protein Phosphatase 1/metabolism , Weight Gain/physiology , Animals , Diet, High-Fat , Eating , Endoplasmic Reticulum Stress , Female , Humans , Insulin Resistance , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation
15.
Nat Commun ; 9(1): 4974, 2018 11 26.
Article in English | MEDLINE | ID: mdl-30478315

ABSTRACT

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity.


Subject(s)
Adipocytes, Brown/metabolism , Adipose Tissue, Brown/blood supply , Adipose Tissue, Brown/innervation , Adrenergic Agents/pharmacology , Bone Morphogenetic Proteins/metabolism , 3T3-L1 Cells , Adipose Tissue, Brown/metabolism , Animals , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Biological , Neovascularization, Physiologic , Neuregulins/genetics , Neuregulins/metabolism , Proteomics , Signal Transduction , Subcutaneous Fat/metabolism , Thermogenesis , Vascular Endothelial Growth Factor A/metabolism
16.
Nucleus ; 9(1): 235-248, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29578370

ABSTRACT

Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure. Recent studies shed some light on how pathogenic A-type lamin variants could trigger lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility. Premature senescence of vascular cells could contribute to cardiovascular complications. In affected families, metabolic alterations occur at an earlier age across generations, which could result from epigenetic deregulation induced by LMNA mutations. Novel cellular models recapitulating adipogenic developmental pathways provide scalable tools for disease modeling and therapeutic screening.


Subject(s)
Lamin Type A/genetics , Lipodystrophy , Mutation , Humans , Lamin Type A/metabolism , Lipodystrophy/drug therapy , Lipodystrophy/genetics , Lipodystrophy/metabolism
17.
Adv Nutr ; 8(5): 694-704, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28916570

ABSTRACT

The incidence of overweight and obesity has reached epidemic proportions, making the control of body weight and its complications a primary health problem. Diet has long played a first-line role in preventing and managing obesity. However, beyond the obvious strategy of restricting caloric intake, growing evidence supports the specific antiobesity effects of some food-derived components, particularly (poly)phenolic compounds. The relatively new rediscovery of active brown adipose tissue in adult humans has generated interest in this tissue as a novel and viable target for stimulating energy expenditure and controlling body weight by promoting energy dissipation. This review critically discusses the evidence supporting the concept that the antiobesity effects ascribed to (poly)phenols might be dependent on their capacity to promote energy dissipation by activating brown adipose tissue. Although discrepancies exist in the literature, most in vivo studies with rodents strongly support the role of some (poly)phenol classes, particularly flavan-3-ols and resveratrol, in promoting energy expenditure. Some human data currently are available and most are consistent with studies in rodents. Further investigation of effects in humans is warranted.


Subject(s)
Adipose Tissue, Brown/physiology , Energy Metabolism , Polyphenols/pharmacology , Adrenergic Agonists/pharmacology , Animals , Anti-Obesity Agents/pharmacology , Body Weight , Diet , Disease Models, Animal , Flavonoids/pharmacology , Humans , Obesity/drug therapy , Resveratrol , Stilbenes/pharmacology , Tea/chemistry , Thermogenesis/drug effects , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism
18.
Mol Nutr Food Res ; 61(9)2017 09.
Article in English | MEDLINE | ID: mdl-28276197

ABSTRACT

SCOPE: Consumption of products rich in flavan-3-ols, such as tea and cocoa, has been associated with decreased obesity, partially dependent on their capacity to enhance energy expenditure. Despite these phenolics having been reported to increase the thermogenic program in brown and white adipose tissue, flavan-3-ols are vastly metabolised in vivo to phenyl-γ-valerolactones. Therefore, we hypothesize that phenyl-γ-valerolactones may directly stimulate the differentiation and the activation of brown adipocytes. METHODS AND RESULTS: Immortalized brown pre-adipocytes were differentiated in presence of (R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL1), (R)-5-(3´-hydroxyphenyl)-γ-valerolactone-4'-O-sulphate (VL2), (R)-5-phenyl-γ-valerolactone-3´,4´-di-O-sulphate (VL3), at concentrations of 2 or 10µM, whereas fully differentiated brown adipocyte were treated acutely (6-24h). None of the treatments regulated the expression levels of the uncouple protein 1, nor of the main transcription factors involved in brown adipogenesis. Similarly, mitochondrial content was unchanged after treatments. Moreover these compounds did not display peroxisome proliferator-activated receptor γ-agonist activity, as evaluated by luciferase assay, and did not enhance norepinephrine-stimulated lipolysis in mature adipocytes. However, both VL1 and VL2 prevented oxidative stress caused by H2 O2 . CONCLUSION: Phenyl-γ-valerolactones and their sulphated forms do not influence brown adipocyte development or function at physiological or supraphysiological doses in vitro, but they are active protecting brown adipocytes from increased reactive oxygen species production.


Subject(s)
Adipocytes, Brown/drug effects , Flavonoids/metabolism , Lactones/pharmacology , Oxidative Stress/drug effects , Adipocytes, Brown/cytology , Adipocytes, Brown/metabolism , Animals , Cell Differentiation/drug effects , Colon/metabolism , Cytoprotection , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , PPAR gamma/agonists
19.
Cell Rep ; 13(10): 2039-47, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26628376

ABSTRACT

Although many transcriptional pathways regulating BAT have been identified, the role of lipid biosynthetic enzymes in thermogenesis has been less investigated. Whereas cold exposure causes changes in the fatty acid composition of BAT, the functional consequences of this remains relatively unexplored. In this study, we demonstrate that the enzyme Elongation of Very Long Chain fatty acids 6 (Elovl6) is necessary for the thermogenic action of BAT. Elovl6 is responsible for converting C16 non-essential fatty acids into C18 species. Loss of Elovl6 does not modulate traditional BAT markers; instead, it causes reduced expression of mitochondrial electron transport chain components and lower BAT thermogenic capacity. The reduction in BAT activity appears to be counteracted by increased beiging of scWAT. When beige fat is disabled by thermoneutrality or aging, Elovl6 KO mice gain weight and have increased scWAT mass and impaired carbohydrate metabolism. Overall, our study suggests fatty acid chain length is important for BAT function.


Subject(s)
Acetyltransferases/metabolism , Adipose Tissue, Brown/metabolism , Fatty Acids/metabolism , Thermogenesis/physiology , Animals , Blotting, Western , Fatty Acid Elongases , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Proteins/metabolism , Real-Time Polymerase Chain Reaction
20.
Curr Diab Rep ; 13(6): 757-67, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24026869

ABSTRACT

Genetic lipodystrophic syndromes are rare diseases characterized by generalized or partial fat atrophy (lipoatrophy) associated with severe metabolic complications such as insulin resistance (IR), diabetes, dyslipidemia, nonalcoholic fatty liver disease, and ovarian hyperandrogenism. During the last 15 years, mutations in several genes have been shown to be responsible for monogenic forms of lipodystrophic syndromes, of autosomal dominant or recessive transmission. Although the molecular basis of lipodystrophies is heterogeneous, most mutated genes lead to impaired adipogenesis, adipocyte lipid storage, and/or formation or maintenance of the adipocyte lipid droplet (LD), showing that primary alterations of adipose tissue (AT) can result in severe systemic metabolic and endocrine consequences. The reduced expandability of AT alters its ability to buffer excess caloric intake, leading to ectopic lipid storage that impairs insulin signaling and other cellular functions ("lipotoxicity"). Genetic studies have also pointed out the close relationships between ageing, inflammatory processes, lipodystrophy, and IR.


Subject(s)
Insulin Resistance/physiology , Lipodystrophy/genetics , Aging/physiology , Animals , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Humans , Inflammation/genetics , Inflammation/physiopathology , Insulin Resistance/genetics , Lipodystrophy/physiopathology
SELECTION OF CITATIONS
SEARCH DETAIL