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1.
Metabolism ; 113: 154396, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33065161

RESUMO

BACKGROUND: Brown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates UCP1-mediated thermogenesis in BAT and causes drastic changes in glucose, lipid, and amino acid metabolism; however, the relationship between these metabolic changes and UCP1-mediated thermogenesis is not fully understood. METHODS: We conducted metabolomic and GeneChip array analyses of BAT after 4-h exposure to cold temperature (10 °C) in wild-type (WT) and UCP1-KO mice. RESULTS: Cold exposure largely increased metabolites of the glycolysis pathway and lactic acid levels in WT, but not in UCP1-KO, mice, indicating that aerobic glycolysis is enhanced as a consequence of UCP1-mediated thermogenesis. GeneChip array analysis of BAT revealed that there were 2865 genes upregulated by cold exposure in WT mice, and 838 of these were upregulated and 74 were downregulated in UCP1-KO mice. Pathway analysis revealed the enrichment of genes involved in fatty acid (FA) ß oxidation and triglyceride (TG) synthesis in both WT and UCP1-KO mice, suggesting that these metabolic pathways were enhanced by cold exposure independently of UCP1-mediated thermogenesis. FA and cholesterol biosynthesis pathways were enhanced only in UCP1-KO mice. Cold exposure also significantly increased the BAT content of proline, tryptophan, and phenylalanine amino acids in both WT and UCP1-KO mice. In WT mice, cold exposure significantly increased glutamine content and enhanced the expression of genes related to glutamine metabolism. Surprisingly, aspartate was almost completely depleted after cold exposure in UCP1-KO mice. Gene expression analysis suggested that aspartate was actively utilized after cold exposure both in WT and UCP1-KO mice, but it was replenished from intracellular N-acetyl-aspartate in WT mice. CONCLUSIONS: These results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.


Assuntos
Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Proteína Desacopladora 1/metabolismo , Animais , Ácidos Graxos/metabolismo , Glutamina/metabolismo , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Termogênese/fisiologia , Triglicerídeos/biossíntese
2.
Nat Commun ; 11(1): 5099, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037202

RESUMO

Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.


Assuntos
Hipertermia Maligna/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Termogênese/fisiologia , Tecido Adiposo Marrom/metabolismo , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , Humanos , Lactente , Lactatos/sangue , Masculino , Hipertermia Maligna/etiologia , Hipertermia Maligna/mortalidade , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estudos Retrospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Termogênese/genética , Proteína Desacopladora 1/genética , Adulto Jovem
3.
Am J Physiol Endocrinol Metab ; 319(5): E912-E922, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32954821

RESUMO

Numerous studies have shown that the recruitment and activation of thermogenic adipocytes, which are brown and beige/brite, reduce the mass of adipose tissue and normalize abnormal glycemia and lipidemia. However, the impact of these adipocytes on the inflammatory state of adipose tissue is still not well understood, especially in response to endotoxemia, which is a major aspect of obesity and metabolic diseases. First, we analyzed the phenotype and metabolic function of white and brite primary adipocytes in response to lipopolysaccharide (LPS) treatment in vitro. Then, 8-wk-old male BALB/c mice were treated for 1 wk with a ß3-adrenergic receptor agonist (CL316,243, 1 mg/kg/day) to induce recruitment and activation of brown and brite adipocytes and were subsequently injected with LPS (Escherichia coli lipopolysaccharide, 100 µg/mouse ip) to generate acute endotoxemia. The metabolic and inflammatory parameters of the mice were analyzed 6 h later. Our results showed that in response to LPS, thermogenic activity promoted a local anti-inflammatory environment with high secretion of IL-1 receptor antagonist (IL-1RA) without affecting other anti- or proinflammatory cytokines. Interestingly, activation of brite adipocytes reduced the LPS-induced secretion of leptin. However, thermogenic activity and adipocyte function were not altered by LPS treatment in vitro or by acute endotoxemia in vivo. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes specifically in response to endotoxemia. This encourages potential therapy involving brown and brite adipocytes for the treatment of obesity and associated metabolic diseases.NEW & NOTEWORTHY Recruitment and activation of brown and brite adipocytes in the adipose tissue of mice lead to a local low-grade anti-inflammatory phenotype in response to acute endotoxemia without alteration of adipocyte phenotype and function.


Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adipogenia/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Termogênese/efeitos dos fármacos , Termogênese/fisiologia
6.
Am J Physiol Cell Physiol ; 319(6): C1158-C1162, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997515

RESUMO

The myosin super-relaxed state (SRX) in skeletal muscle is hypothesized to play an important role in regulating muscle contractility and thermogenesis in humans but has only been examined in model organisms. Here we report the first human skeletal muscle SRX measurements, using quantitative epifluorescence microscopy of fluorescent 2'/3'-O-(N-methylanthraniloyl) ATP (mantATP) single-nucleotide turnover. Myosin heavy chain (MHC) isoform expression was determined using gel electrophoresis for each permeabilized vastus lateralis fiber, to allow for novel comparisons of SRX between fiber types. We find that the fraction of myosin in SRX is less in MHC IIA fibers than in MHC I and IIAX fibers (P = 0.008). ATP turnover of SRX is faster in MHC IIAX fibers compared with MHC I and IIA fibers (P = 0.001). We conclude that SRX biochemistry is measurable in human skeletal muscle, and our data indicate that SRX depends on fiber type as classified by MHC isoform. Extension from this preliminary work would provide further understanding regarding the role of SRX in human muscle physiology.


Assuntos
Contração Muscular/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Termogênese/fisiologia , Adulto , Humanos , Isoformas de Proteínas/metabolismo , Músculo Quadríceps/citologia , Músculo Quadríceps/metabolismo , Adulto Jovem
7.
Nat Commun ; 11(1): 4837, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973183

RESUMO

ATP synthesis and thermogenesis are two critical outputs of mitochondrial respiration. How these outputs are regulated to balance the cellular requirement for energy and heat is largely unknown. Here we show that major facilitator superfamily domain containing 7C (MFSD7C) uncouples mitochondrial respiration to switch ATP synthesis to thermogenesis in response to heme. When heme levels are low, MSFD7C promotes ATP synthesis by interacting with components of the electron transport chain (ETC) complexes III, IV, and V, and destabilizing sarcoendoplasmic reticulum Ca2+-ATPase 2b (SERCA2b). Upon heme binding to the N-terminal domain, MFSD7C dissociates from ETC components and SERCA2b, resulting in SERCA2b stabilization and thermogenesis. The heme-regulated switch between ATP synthesis and thermogenesis enables cells to match outputs of mitochondrial respiration to their metabolic state and nutrient supply, and represents a cell intrinsic mechanism to regulate mitochondrial energy metabolism.


Assuntos
Trifosfato de Adenosina/metabolismo , Heme/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/metabolismo , Receptores Virais/metabolismo , Termogênese/fisiologia , Animais , Deficiência de Citocromo-c Oxidase , Complexo III da Cadeia de Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons , Metabolismo Energético/fisiologia , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membranas Mitocondriais/metabolismo , Domínios Proteicos , Receptores Virais/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais , Células THP-1
8.
Proc Natl Acad Sci U S A ; 117(36): 22413-22422, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32839323

RESUMO

Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a ß3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.


Assuntos
Adipócitos Bege/fisiologia , Adipócitos Marrons/fisiologia , Histona-Lisina N-Metiltransferase , Termogênese/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Animais , Dieta Hiperlipídica , Feminino , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/genética
9.
Proc Natl Acad Sci U S A ; 117(36): 22544-22551, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32826330

RESUMO

Obesity is a major health problem worldwide, given its growing incidence and its association with a variety of comorbidities. Weight gain results from an increase in energy intake without a concomitant increase in energy expenditure. To combat the obesity epidemic, many studies have focused on the pathways underlying satiety and hunger signaling, while other studies have concentrated on the mechanisms involved in energy expenditure, most notably adaptive thermogenesis. Hypothyroidism in humans is typically associated with a decreased basal metabolic rate, lower energy expenditure, and weight gain. However, hypothyroid mouse models have been reported to have a leaner phenotype than euthyroid controls. To elucidate the mechanism underlying this phenomenon, we used a drug-free mouse model of hypothyroidism: mice lacking the sodium/iodide symporter (NIS), the plasma membrane protein that mediates active iodide uptake in the thyroid. In addition to being leaner than euthyroid mice, owing in part to reduced food intake, these hypothyroid mice show signs of compensatory up-regulation of the skeletal-muscle adaptive thermogenic marker sarcolipin, with an associated increase in fatty acid oxidation (FAO). Neither catecholamines nor thyroid-stimulating hormone (TSH) are responsible for sarcolipin expression or FAO stimulation; rather, thyroid hormones are likely to negatively regulate both processes in skeletal muscle. Our findings indicate that hypothyroidism in mice results in a variety of metabolic changes, which collectively lead to a leaner phenotype. A deeper understanding of these changes may make it possible to develop new strategies against obesity.


Assuntos
Hipotireoidismo/metabolismo , Músculo Esquelético/metabolismo , Termogênese/fisiologia , Animais , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/metabolismo , Fenótipo , Proteolipídeos/metabolismo , Simportadores/genética , Simportadores/metabolismo
10.
Am J Physiol Endocrinol Metab ; 319(2): E401-E409, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32634320

RESUMO

Adipose tissue plays a central role in regulating whole body energy and glucose homeostasis at both organ and systemic levels. Inositol polyphosphates, such as 5-diphosphoinositol pentakisphosphate, reportedly control adipocyte functions and energy expenditure. However, the physiological roles of the inositol polyphosphate (IP) pathway in the adipose tissue are not yet fully defined. The aim of the present study was to test the hypothesis that inositol polyphosphate multikinase (IPMK), a key enzyme in the IP metabolism, plays a critical role in adipose tissue biology and obesity. We generated adipocyte-specific IPMK knockout (Ipmk AKO) mice and evaluated metabolic phenotypes by measuring fat accumulation, glucose homeostasis, and insulin sensitivity in adult mice fed either a regular-chow diet or high-fat diet (HFD). Despite substantial reduction of IPMK, Ipmk AKO mice exhibited normal glucose tolerance and insulin sensitivity and did not show changes in fat accumulation in response to HFD-feeding. In addition, loss of IPMK had no major impact on thermogenic processes in response to cold exposure. Collectively, these findings suggest that adipocyte IPMK is dispensable for normal adipose tissue and its physiological functions in whole body metabolism, suggesting the complex roles that inositol polyphosphate metabolism has in the regulation of adipose tissue.


Assuntos
Adipócitos/enzimologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Tecido Adiposo/fisiologia , Tecido Adiposo Marrom/fisiologia , Animais , Temperatura Baixa , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Obesidade/enzimologia , Obesidade/etiologia , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Termogênese/fisiologia
11.
Nat Commun ; 11(1): 3347, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620768

RESUMO

A sharp increase in mitochondrial Ca2+ marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca2+ deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca2+ extrusion via the mitochondrial Na+/Ca2+ exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging of glucose uptake and VO2 measurements confirm a thermogenic defect in NCLX-null mice. We show that Ca2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the mitochondrial permeability transition pore (mPTP) opening, leading to a remarkable mitochondrial swelling and cell death. Treatment with mPTP inhibitors rescue mitochondrial function and thermogenesis in NCLX-null BAT, while calcium overload persists. Our findings identify a key pathway through which BA evade apoptosis during adrenergic stimulation of uncoupling. NCLX deletion transforms the adrenergic pathway responsible for thermogenesis activation into a death pathway.


Assuntos
Adipócitos Marrons/patologia , Tecido Adiposo Marrom/metabolismo , Norepinefrina/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Termogênese/fisiologia , Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/citologia , Adrenérgicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Temperatura Baixa/efeitos adversos , Ciclosporina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Microscopia Intravital , Masculino , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Cultura Primária de Células , Transdução de Sinais , Trocador de Sódio e Cálcio/genética , Termogênese/efeitos dos fármacos
12.
Diabetes ; 69(8): 1599-1604, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32690661

RESUMO

Adipose tissue serves as the body's primary energy storage site; however, findings in recent decades have transformed our understanding of the multifaceted roles of this adaptable organ. The ability of adipose tissue to undergo energy expenditure through heat generation is termed adaptive thermogenesis, a process carried out by thermogenic adipocytes. Adipocytes are the primary parenchymal cell type in adipose tissue, yet these cells are sustained within a rich stromal vascular microenvironment comprised of adipose stem cells and progenitors, immune cells, neuronal cells, fibroblasts, and endothelial cells. Intricate cross talk between these diverse cell types is essential in regulating the activation of thermogenic fat, and the past decade has shed significant light on how this intercellular communication functions. This review will draw upon recent findings and current perspectives on the sophisticated repertoire of cellular and molecular features that comprise the adipose thermogenic milieu.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Calefação , Termogênese/fisiologia , Animais , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Humanos , Modelos Biológicos , Termogênese/genética
13.
Nat Rev Endocrinol ; 16(8): 421-436, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32493980

RESUMO

Perturbations in metabolic processes are associated with diseases such as obesity, type 2 diabetes mellitus, certain infections and some cancers. A resurgence of interest in creatine biology is developing, with new insights into a diverse set of regulatory functions for creatine. This resurgence is primarily driven by technological advances in genetic engineering and metabolism as well as by the realization that this metabolite has key roles in cells beyond the muscle and brain. Herein, we highlight the latest advances in creatine biology in tissues and cell types that have historically received little attention in the field. In adipose tissue, creatine controls thermogenic respiration and loss of this metabolite impairs whole-body energy expenditure, leading to obesity. We also cover the various roles that creatine metabolism has in cancer cell survival and the function of the immune system. Renewed interest in this area has begun to showcase the therapeutic potential that lies in understanding how changes in creatine metabolism lead to metabolic disease.


Assuntos
Creatina/metabolismo , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Imunidade/fisiologia , Neoplasias/metabolismo , Tecido Adiposo/metabolismo , Animais , Creatina/fisiologia , Creatina Quinase/genética , Expressão Gênica , Humanos , Macrófagos , Doenças Metabólicas , Obesidade/metabolismo , Linfócitos T , Termogênese/fisiologia , Proteína Desacopladora 1
14.
Nat Commun ; 11(1): 2847, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504036

RESUMO

The browning of white adipose tissue (WAT) has got much attention for its potential beneficial effects on metabolic disorders, however, the nutritional factors and neuronal signals involved remain largely unknown. We sought to investigate whether WAT browning is stimulated by leucine deprivation, and whether the amino acid sensor, general control non-derepressible 2 (GCN2), in amygdalar protein kinase C-δ (PKC-δ) neurons contributes to this regulation. Our results show that leucine deficiency can induce WAT browning, which is unlikely to be caused by food intake, but is largely blocked by PKC-δ neuronal inhibition and amygdalar GCN2 deletion. Furthermore, GCN2 knockdown in amygdalar PKC-δ neurons blocks WAT browning, which is reversed by over-expression of amino acid responsive gene activating transcription factor 4 (ATF4), and is mediated by the activities of amygdalar PKC-δ neurons and the sympathetic nervous system. Our data demonstrate that GCN2/ATF4 can regulate WAT browning in amygdalar PKC-δ neurons under leucine deprivation.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Tecido Adiposo Branco/fisiologia , Tonsila do Cerebelo/fisiologia , Leucina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/inervação , Tonsila do Cerebelo/citologia , Animais , Técnicas de Silenciamento de Genes , Lipólise/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Proteína Quinase C-delta/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/fisiologia , Técnicas Estereotáxicas , Sistema Nervoso Simpático/fisiologia , Termogênese/fisiologia
15.
J Vis Exp ; (160)2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32597845

RESUMO

Foraging and feeding behaviors allow animals to access sources of energy and nutrients essential for their development, health, and fitness. Investigating the neuronal regulation of these behaviors is essential for the understanding of the physiological and molecular mechanisms underlying nutritional homeostasis. The use of genetically tractable animal models such as worms, flies, and fish greatly facilitates these types of studies. In the last decade, the fruit fly Drosophila melanogaster has been used as a powerful animal model by neurobiologists investigating the neuronal control of feeding and foraging behaviors. While undoubtedly valuable, most studies examine adult flies. Here, we describe a protocol that takes advantage of the simpler larval nervous system to investigate neuronal substrates controlling feeding behaviors when larvae are exposed to diets differing in their protein and carbohydrates content. Our methods are based on a quantitative colorimetric no-choice feeding assay, performed in the context of a neuronal thermogenetic-activation screen. As a read-out, the amount of food eaten by larvae over a 1 h interval was used when exposed to one of the three dye-labeled diets that differ in their protein to carbohydrates (P:C) ratios. The efficacy of this protocol is demonstrated in the context of a neurogenetic screen in larval Drosophila, by identifying candidate neuronal populations regulating the amount of food eaten in diets of different macronutrient quality. We were also able to classify and group the genotypes tested into phenotypic classes. Besides a brief review of the currently available methods in the literature, the advantages and limitations of these methods are discussed and, also, some suggestions are provided about how this protocol might be adapted to other specific experiments.


Assuntos
Drosophila melanogaster/fisiologia , Comportamento Alimentar/fisiologia , Neurônios/fisiologia , Nutrientes/metabolismo , Termogênese/fisiologia , Análise de Variância , Animais , Colorimetria , Dieta , Drosophila melanogaster/genética , Larva/fisiologia , Modelos Animais , Fenótipo
16.
Biochem J ; 477(11): 2071-2093, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32539124

RESUMO

Metabolic inflexibility, defined as the inability to respond or adapt to metabolic demand, is now recognised as a driving factor behind many pathologies associated with obesity and the metabolic syndrome. Adipose tissue plays a pivotal role in the ability of an organism to sense, adapt to and counteract environmental changes. It provides a buffer in times of nutrient excess, a fuel reserve during starvation and the ability to resist cold-stress through non-shivering thermogenesis. Recent advances in single-cell RNA sequencing combined with lineage tracing, transcriptomic and proteomic analyses have identified novel adipocyte progenitors that give rise to specialised adipocytes with diverse functions, some of which have the potential to be exploited therapeutically. This review will highlight the common and distinct functions of well-known adipocyte populations with respect to their lineage and plasticity, as well as introducing the most recent members of the adipocyte family and their roles in whole organism energy homeostasis. Finally, this article will outline some of the more preliminary findings from large data sets generated by single-cell transcriptomics of mouse and human adipose tissue and their implications for the field, both for discovery and for therapy.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Termogênese/fisiologia , Adipócitos/citologia , Tecido Adiposo Marrom/citologia , Animais , Humanos , Camundongos
17.
Eur J Endocrinol ; 183(3): 343-355, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32508310

RESUMO

Objective: Retrospective studies suggest that women have more active brown adipose tissue (BAT) than men, but little is known of the effect of fluctuating sex steroids across the menstrual cycle on thermogenesis in women. Design: To characterise the effects of sex and sex steroids on BAT activity we recruited healthy weight men (n = 14) and women at two stages of the menstrual cycle (luteal, n = 9; follicular, n = 11). Methods: Infrared thermography measured supraclavicular temperature to index BAT thermogenesis in response to both cold (immersion of one hand in water at 15°C) and meal (Ensure, 10 kcal/kg body weight) stimuli. Results: Adaptive BAT temperature responses were greater (P < 0.05) in women than men, irrespective of stage of menstrual cycle. Whereas during cold exposure, the increase in BAT temperature was abrogated (P < 0.05) in women during follicular phase compared to men and women during luteal phase. Plasma concentrations of progesterone, 17ß-estradiol, testosterone and cortisol were measured. Regression analyses demonstrated that baseline BAT temperature was positively correlated (P < 0.05) with progesterone levels, but was inversely associated (P < 0.05) with cortisol concentration. Both cold- and meal-induced changes in BAT temperature mildly correlated (P = 0.07; P < 0.05) with 17ß-estradiol levels, but not with testosterone concentrations. Conclusions: Baseline supraclavicular temperature is elevated in women during the luteal phase of the menstrual cycle, which correlated with elevated progesterone concentrations. Women exhibited greater thermogenic responses than men, irrespective of the state of the menstrual cycle, which was associated with plasma levels of 17ß-estradiol. We conclude that sex steroids may regulate BAT thermogenesis in healthy adults.


Assuntos
Tecido Adiposo Marrom/fisiologia , Hormônios Esteroides Gonadais/fisiologia , Caracteres Sexuais , Termogênese/fisiologia , Adulto , Temperatura Corporal/fisiologia , Temperatura Baixa , Estradiol/sangue , Feminino , Fase Folicular/fisiologia , Humanos , Fase Luteal/fisiologia , Masculino , Refeições , Ciclo Menstrual/fisiologia , Estudos Retrospectivos , Testosterona/sangue , Adulto Jovem
18.
Nat Metab ; 2(5): 397-412, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32440655

RESUMO

Human thermogenic adipose tissue mitigates metabolic disease, raising much interest in understanding its development and function. Here, we show that human thermogenic adipocytes specifically express a primate-specific long non-coding RNA, LINC00473 which is highly correlated with UCP1 expression and decreased in obesity and type-2 diabetes. LINC00473 is detected in progenitor cells, and increases upon differentiation and in response to cAMP. In contrast to other known adipocyte LincRNAs, LINC00473 shuttles out of the nucleus, colocalizes and can be crosslinked to mitochondrial and lipid droplet proteins. Up- or down- regulation of LINC00473 results in reciprocal alterations in lipolysis, respiration and transcription of genes associated with mitochondrial oxidative metabolism. Depletion of PLIN1 results in impaired cAMP-responsive LINC00473 expression and lipolysis, indicating bidirectional interactions between PLIN1, LINC00473 and mitochondrial oxidative functions. Thus, we suggest that LINC00473 is a key regulator of human thermogenic adipocyte function, and reveals a role for a LincRNA in inter-organelle communication and human energy metabolism.


Assuntos
Adipócitos/fisiologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia , Termogênese/genética , Termogênese/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação Celular/genética , Comunicação Celular/fisiologia , Núcleo Celular/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Gotículas Lipídicas , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Consumo de Oxigênio/genética , Consumo de Oxigênio/fisiologia , Perilipina-1/deficiência , Perilipina-1/genética , Proteína Desacopladora 1/biossíntese , Proteína Desacopladora 1/genética , Adulto Jovem
19.
Nat Commun ; 11(1): 1730, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265443

RESUMO

Cold stimuli and the subsequent activation of ß-adrenergic receptor (ß-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the ß3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the ß-AR pathway and triggers Ca2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Channelrhodopsins/metabolismo , Obesidade/terapia , Optogenética/instrumentação , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Termogênese/efeitos da radiação , Adipócitos/efeitos da radiação , Tecido Adiposo/efeitos da radiação , Animais , Peso Corporal/fisiologia , Peso Corporal/efeitos da radiação , Cálcio/metabolismo , Células Cultivadas , Channelrhodopsins/efeitos da radiação , Channelrhodopsins/uso terapêutico , Dieta , Metabolismo Energético/efeitos da radiação , Locomoção , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Optogenética/métodos , Consumo de Oxigênio , Receptores Adrenérgicos beta/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Termogênese/fisiologia
20.
Biochem J ; 477(7): 1261-1286, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32271883

RESUMO

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/anatomia & histologia , Tecido Adiposo Marrom/diagnóstico por imagem , Animais , Metabolismo Energético/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Termogênese/fisiologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Triglicerídeos/metabolismo
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