RESUMO
Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress-induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15-dependent daytime-restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress-induced GDF15 in the regulation of systemic energy metabolism.
Assuntos
Anorexia , Fator 15 de Diferenciação de Crescimento , Tecido Adiposo Branco/metabolismo , Animais , Anorexia/genética , Anorexia/metabolismo , Metabolismo Energético , Fator 15 de Diferenciação de Crescimento/genética , Fator 15 de Diferenciação de Crescimento/metabolismo , Camundongos , Mitocôndrias/metabolismoRESUMO
In endothermic species, heat released as a product of metabolism ensures stable internal temperature throughout the organism, despite varying environmental conditions. Mitochondria are major actors in this thermogenic process. Part of the energy released by the oxidation of respiratory substrates drives ATP synthesis and metabolite transport, but a substantial proportion is released as heat. Using a temperature-sensitive fluorescent probe targeted to mitochondria, we measured mitochondrial temperature in situ under different physiological conditions. At a constant external temperature of 38 °C, mitochondria were more than 10 °C warmer when the respiratory chain (RC) was fully functional, both in human embryonic kidney (HEK) 293 cells and primary skin fibroblasts. This differential was abolished in cells depleted of mitochondrial DNA or treated with respiratory inhibitors but preserved or enhanced by expressing thermogenic enzymes, such as the alternative oxidase or the uncoupling protein 1. The activity of various RC enzymes was maximal at or slightly above 50 °C. In view of their potential consequences, these observations need to be further validated and explored by independent methods. Our study prompts a critical re-examination of the literature on mitochondria.
Assuntos
Mitocôndrias/fisiologia , Termogênese/fisiologia , Fibroblastos/fisiologia , Corantes Fluorescentes , Células HEK293 , Temperatura Alta , Humanos , Membranas Mitocondriais/fisiologia , Proteínas Mitocondriais/metabolismo , Oxirredutases/metabolismo , Proteínas de Plantas/metabolismo , Cultura Primária de Células , Pele , Temperatura , Proteína Desacopladora 1/metabolismoRESUMO
Brown adipose tissue (BAT) enables adaptive thermoregulation through heat production that is catalyzed by mitochondrial uncoupling protein 1 (UCP1). BAT is frequently studied in rodent model organisms, and recently in adult humans to treat metabolic diseases. However, complementary studies of many non-model species, which have diversified to many more ecological niches, may significantly broaden our understanding of BAT regulation and its physiological roles. This Review highlights the research on non-model organisms, which was instrumental to the discovery of BAT function, and the unique evolutionary history of BAT/UCP1 in mammalian thermogenesis. The comparative biology of BAT provides a powerful integrative approach that could identify conserved and specialized functional changes in BAT and UCP1 by considering species diversity, ecology and evolution, and by fusing multiple scientific disciplines such as physiology and biochemistry. Thus, resolving the complete picture of BAT biology may fail if comparative studies of non-model organisms are neglected.
Assuntos
Tecido Adiposo Marrom/metabolismo , Evolução Biológica , Mamíferos/fisiologia , Termogênese/fisiologia , Proteína Desacopladora 1/genética , Animais , Proteína Desacopladora 1/metabolismoRESUMO
Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with mitochondrial perturbations in SM, triggering an increased protein turnover and amino acid metabolism with induced biosynthetic serine/1-carbon/glycine pathway and the longevity-promoting polyamine spermidine as well as the trans-sulfuration pathway. This is related to an induction of NADPH-generating pathways and glutathione metabolism as an adaptive mitohormetic response and defense against increased oxidative stress. Strikingly, consistent muscle retrograde signaling profiles were observed in acute stress states such as muscle cell starvation and lipid overload, muscle regeneration, and heart muscle inflammation, but not in response to exercise. We provide conclusive evidence for a key compensatory stress-signaling network that preserves cellular function, oxidative stress tolerance, and survival during conditions of increased SM mitochondrial distress, a metabolic reprogramming profile so far only demonstrated for cancer cells and heart muscle.
Assuntos
Glicina/metabolismo , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Serina/metabolismo , Animais , Sobrevivência Celular/fisiologia , Hormese , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Redes e Vias Metabólicas , Camundongos , Camundongos Transgênicos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fibras Musculares de Contração Rápida/metabolismo , Proteínas Musculares/metabolismo , Estresse Oxidativo , Transdução de Sinais , Transcriptoma , Proteína Desacopladora 1RESUMO
The presence of two distinct types of adipose tissue, which have opposing functions, has been known for decades. White adipose tissue (WAT) is the main tissue of energy storage, while brown adipose tissue (BAT) dissipates energy as heat and is required for non-shivering thermoregulation. In the last few years, a third type of adipocyte was identified, termed the brite ("brown and white") or beige adipocyte. Their physiological control and role, however, are not fully clarified. Brite/beige adipocytes have a positive impact on systemic metabolism that is generally explained by the thermogenesis of brite/beige adipocytes; although thermogenesis has not been directly measured but is mostly inferred by gene expression data of typical thermogenic genes such as uncoupling protein 1 (UCP1). Here we critically review functional evidence for the thermogenic potential of brite/beige adipocytes, leading to the conclusion that direct measurements of brite/beige adipocyte bioenergetics, beyond gene regulation, are pivotal to quantify their thermogenic potential. In particular, we exemplified that the massive induction of UCP1 mRNA during the browning of isolated subcutaneous adipocytes in vitro is not reflected in significant alterations of cellular bioenergetics. Herein, we demonstrate that increases in mitochondrial respiration in response to beta-adrenergic stimulus can be independent of UCP1. Using HEK293 cells expressing UCP1, we show how to directly assess UCP1 function by adequate activation in intact cells. Finally, we provide a guide on the interpretation of UCP1 activity and the pitfalls by solely using respiration measurements. The functional analysis of beige adipocyte bioenergetics will assist to delineate the impact of browning on thermogenesis, possibly elucidating additional physiological roles and its contribution to systemic metabolism, highlighting possible avenues for future research. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
Assuntos
Tecido Adiposo/metabolismo , Canais Iônicos/metabolismo , Proteínas Mitocondriais/metabolismo , Termogênese , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/fisiologia , Animais , Respiração Celular , Células Cultivadas , Células HEK293 , Humanos , Canais Iônicos/genética , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rosiglitazona , Tiazolidinedionas/farmacologia , Proteína Desacopladora 1RESUMO
UCP1-Tg mice with ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2α/ATF4) in SM. Targeting mitochondrial function in vitro by treating C2C12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, ß-klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Canais Iônicos/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Composição Corporal/fisiologia , Densidade Óssea/fisiologia , Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/farmacologia , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Canais Iônicos/genética , Camundongos , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/genética , Músculo Esquelético/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Fosforilação , Desacopladores/farmacologia , Proteína Desacopladora 1RESUMO
The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as "batokines", which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.
Assuntos
Tecido Adiposo Marrom , Doenças Metabólicas , Humanos , Tecido Adiposo Marrom/metabolismo , Obesidade/metabolismo , Metabolismo Energético/fisiologia , Doenças Metabólicas/metabolismo , Transdução de Sinais , Termogênese/fisiologiaRESUMO
Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials.
Assuntos
Tecido Adiposo Marrom , Evolução Biológica , Marsupiais , Termogênese , Proteína Desacopladora 1 , Animais , Humanos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Eutérios/genética , Eutérios/fisiologia , Evolução Molecular , Marsupiais/genética , Marsupiais/fisiologia , Filogenia , Termogênese/genética , Transcriptoma , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Fibroblast growth factor 21 (FGF21) is generally known as a stress-induced metabolic regulator with enormous therapeutic potential to treat metabolic diseases, but a more specific role of FGF21 concerns physiological handling of alcohol in mammals. In this issue of Cell Metabolism, Choi et al. demonstrate that FGF21 mediates the recovery from alcohol intoxication by directly activating noradrenergic neurons in mice, thus advancing our knowledge on FGF21 biology and further diversifying its therapeutic potential.
Assuntos
Intoxicação Alcoólica , Doenças Metabólicas , Camundongos , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Etanol , Mamíferos/metabolismoRESUMO
Mice with ectopic expression of uncoupling protein-1 (UCP1) in skeletal muscle exhibit a healthy aging phenotype with increased longevity and resistance to impaired metabolic health. This may be achieved by decreasing protein glycation by the reactive metabolite, methylglyoxal (MG). We investigated protein glycation and oxidative damage in skeletal muscle of mice with UCP1 expression under control of the human skeletal actin promoter (HSA-mUCP1) at age 12 weeks (young) and 70 weeks (aged). We found both young and aged HSA-mUCP1 mice had decreased advanced glycation endproducts (AGEs) formed from MG, lysine-derived Nε(1-carboxyethyl)lysine (CEL) and arginine-derived hydroimidazolone, MG-H1, whereas protein glycation by glucose forming Nε-fructosyl-lysine (FL) was increased ca. 2-fold, compared to wildtype controls. There were related increases in FL-linked AGEs, Nε-carboxymethyl-lysine (CML) and 3-deoxylglucosone-derived hydroimidazolone 3DG-H, and minor changes in protein oxidative and nitration adducts. In aged HSA-mUCP1 mice, urinary MG-derived AGEs/FL ratio was decreased ca. 60% whereas there was no change in CML/FL ratio - a marker of oxidative damage. This suggests that, normalized for glycemic status, aged HSA-mUCP1 mice had a lower flux of whole body MG-derived AGE exposure compared to wildtype controls. Proteomics analysis of skeletal muscle revealed a shift to increased heat shock proteins and mechanoprotection and repair in HSA-mUCP1 mice. Decreased MG-derived AGE protein content in skeletal muscle of aged HSA-mUCP1 mice is therefore likely produced by increased proteolysis of MG-modified proteins and increased proteostasis surveillance of the skeletal muscle proteome. From this and previous transcriptomic studies, signaling involved in enhanced removal of MG-modified protein is likely increased HSPB1-directed HUWE1 ubiquitination through eIF2α-mediated, ATF5-induced increased expression of HSPB1. Decreased whole body exposure to MG-derived AGEs may be linked to increased weight specific physical activity of HSA-mUCP1 mice. Decreased formation and increased clearance of MG-derived AGEs may be associated with healthy aging in the HSA-mUCP1 mouse.
Assuntos
Produtos Finais de Glicação Avançada , Envelhecimento Saudável , Humanos , Camundongos , Animais , Idoso , Lactente , Produtos Finais de Glicação Avançada/metabolismo , Lisina/metabolismo , Aldeído Pirúvico/metabolismo , Reação de Maillard , Proteína Desacopladora 1/metabolismo , Expressão Ectópica do Gene , Proteínas/metabolismo , Músculo Esquelético/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is widely investigated to correct diet-induced obesity (DIO). Paradoxically, UCP1-deficient male mice are resistant to DIO at room temperature. Recently, we uncovered a key role for fibroblast growth factor 21 (FGF21), a promising drug target for treatment of metabolic disease, in this phenomenon. As the metabolic action of FGF21 is so far understudied in females, we aim to investigate potential sexual dimorphisms. Here, we confirm that male UCP1 KO mice display resistance to DIO in mild cold, without significant changes in metabolic parameters. Surprisingly, females gained the same amount of body fat as WT controls. Molecular regulation was similar between UCP1 KO males and females, with an upregulation of serum FGF21, coinciding with beiging of inguinal white adipose tissue and induced lipid metabolism. While energy expenditure did not display significant differences, UCP1 KO females significantly increased their food intake. Altogether, our results indicate that hyperphagia is likely counteracting the beneficial effects of FGF21 in female mice. This underlines the importance of sex-specific studies in (pre)clinical research for personalized drug development.
Assuntos
Hiperfagia , Obesidade , Proteína Desacopladora 1 , Animais , Feminino , Masculino , Camundongos , Hiperfagia/tratamento farmacológico , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Metabolic diseases represent the major health burden of our modern society. With the need of novel therapeutic approaches, fibroblast growth factor 21 (FGF21) is a promising target, based on metabolic improvements upon FGF21 administration in mice and humans. Endogenous FGF21 serum levels, however, are increased during obesity-related diseases, suggesting the development of FGF21 resistance during obesity and thereby lowering FGF21 efficacy. In uncoupling protein 1 knockout (UCP1 KO) mice, however, elevated endogenous FGF21 levels mediate resistance against diet-induced obesity. Here, we show that after long-term high fat diet feeding (HFD), circulating FGF21 levels become similarly high in obese wildtype and obesity-resistant UCP1 KO mice, suggesting improved FGF21 sensitivity in UCP1 KO mice. To test this hypothesis, we injected FGF21 after long-term HFD and assessed the metabolic and molecular effects. The UCP1 KO mice lost weight directly upon FGF21 administration, whereas body weights of WT mice resisted weight loss in the initial phase of the treatment. The FGF21 treatment induced expression of liver Pck1, a typical FGF21-responsive gene, in both genotypes. In iWAT, FGF21-responsive genes were selectively induced in UCP1 KO mice, strongly associating FGF21-sensitivity in iWAT with healthy body weights. Thus, these data support the concept that FGF21-sensitivity in adipose tissue is key for metabolic improvements during obesogenic diets.
Assuntos
Tecido Adiposo , Obesidade , Animais , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos , Humanos , Camundongos , Camundongos Knockout , Proteína Desacopladora 1RESUMO
OBJECTIVE: Uncoupling protein 1 (UCP1) catalyses mitochondrial proton leak in brown adipose tissue to facilitate nutrient oxidation for heat production, and may combat metabolic disease if activated in humans. During the adrenergic stimulation of brown adipocytes, free fatty acids generated from lipolysis activate UCP1 via an unclear interaction. Here, we set out to characterise activator binding to purified UCP1 to clarify the activation process, discern novel activators and the potential to target UCP1. METHODS: We assessed ligand binding to purified UCP1 by protein thermostability shift analysis, which unlike many conventional approaches can inform on the binding of hydrophobic ligands to membrane proteins. A detailed activator interaction analysis and screening approach was carried out, supported by investigations of UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1 expression-controlled cell lines. RESULTS: We reveal that fatty acids and other activators influence UCP1 through a specific destabilising interaction, behaving as transport substrates that shift the protein to a less stable conformation of a transport cycle. Through the detection of specific stability shifts in screens, we identify novel activators, including the over-the-counter drug ibuprofen, where ligand analysis indicates that UCP1 has a relatively wide structural specificity for interacting molecules. Ibuprofen successfully induced UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1-expressing HEK293 cells but not in cultured brown adipocytes, suggesting drug delivery differs in each cell type. CONCLUSIONS: These findings clarify the nature of the activator-UCP1 interaction and demonstrate that the targeting of UCP1 in cells by approved drugs is in principle achievable as a therapeutic avenue, but requires variants with more effective delivery in brown adipocytes.
Assuntos
Lipossomos , Proteínas de Membrana , Proteína Desacopladora 1 , Células HEK293 , Humanos , Ibuprofeno , Canais Iônicos/metabolismo , Ligantes , Lipossomos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Proteína Desacopladora 1/metabolismoRESUMO
Mitochondrial uncoupling in skeletal muscle has raised a major interest as a therapeutic target for treatment of obesity, insulin sensitivity, and age-related disease. These physiological effects could be demonstrated in several mouse models ectopically expressing uncoupling protein 1 (UCP1). Here, we investigated whether UCP1 expressed under the control of the human skeletal actin (HSA) promoter in mouse skeletal muscle can be regulated, and whether it affects mitochondrial superoxide production. We show that the skeletal muscle UCP1 can be fully inhibited by a purine nucleotide (GDP) and reactivated by fatty acids (palmitate). During mitochondrial resting state (State 4), mitochondrial superoxide production is about 76% lower in transgenic mice. We suggest that this reduction is due to uncoupling activity as the administration of GDP restores superoxide production to wildtype levels. Our study confirms native behaviour of UCP1 in skeletal muscle and demonstrates beneficial effects on prevention of mitochondrial reactive oxygen species production which may reduce age-related deleterious processes.
Assuntos
Canais Iônicos/fisiologia , Mitocôndrias Musculares/metabolismo , Proteínas Mitocondriais/fisiologia , Músculo Esquelético/metabolismo , Prótons , Superóxidos/metabolismo , Animais , Feminino , Guanosina Difosfato/farmacologia , Humanos , Peróxido de Hidrogênio/metabolismo , Cinética , Masculino , Camundongos , Camundongos Transgênicos , Translocases Mitocondriais de ADP e ATP/metabolismo , Músculo Esquelético/citologia , Oxidantes/metabolismo , Oxigênio/metabolismo , Palmitatos/metabolismo , Ácido Succínico/metabolismo , Proteína Desacopladora 1RESUMO
Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are established as stress-responsive cytokines that can modulate energy balance by increasing energy expenditure or suppressing food intake, respectively. Despite their pharmacologically induced beneficial effects on obesity and comorbidities, circulating levels of both cytokines are elevated during obesity and related metabolic complications. On the other hand, endocrine crosstalk via FGF21 and GDF15 was also reported to play a crucial role in genetically modified mouse models of mitochondrial perturbations leading to diet-induced obesity (DIO) resistance. This review aims to dissect the complexities of endogenous FGF21 and GDF15 action in obesity versus DIO resistance for the regulation of energy balance in metabolic health and disease.
Assuntos
Fatores de Crescimento de Fibroblastos , Fator 15 de Diferenciação de Crescimento/metabolismo , Animais , Metabolismo Energético/fisiologia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Camundongos , Obesidade/metabolismo , Estresse FisiológicoRESUMO
Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. Although increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Recently, UCP1 high and low expressing brown adipocytes were identified, but a developmental origin of these subtypes has not been studied. To obtain more insights into brown preadipocyte heterogeneity, we use single-cell RNA sequencing of the BAT stromal vascular fraction of C57/BL6 mice and characterize brown preadipocyte and adipocyte clonal cell lines. Statistical analysis of gene expression profiles from brown preadipocyte and adipocyte clones identify markers distinguishing brown adipocyte subtypes. We confirm the presence of distinct brown adipocyte populations in vivo using the markers EIF5, TCF25, and BIN1. We also demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that BIN1 marks dormant brown adipocytes. The existence of multiple brown adipocyte subtypes suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct functions in thermogenesis and the regulation of whole body energy homeostasis.
Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Transcriptoma , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA-Seq/métodos , Transdução de Sinais/genética , Análise de Célula Única/métodos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.
Assuntos
Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Polipeptídeo Inibidor Gástrico/farmacologia , Receptores dos Hormônios Gastrointestinais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Sistema Nervoso Central/metabolismo , Dieta Hiperlipídica , Polipeptídeo Inibidor Gástrico/química , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/metabolismo , Obesidade/patologia , Obesidade/prevenção & controle , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores dos Hormônios Gastrointestinais/deficiência , Receptores dos Hormônios Gastrointestinais/genéticaRESUMO
Fibroblast growth factor 21 (FGF21) is in biomedical focus as a treatment option for metabolic diseases, given that administration improves metabolism in mice and humans. The metabolic effects of exogenous FGF21 administration are well-characterized, but the physiological role of endogenous FGF21 has not been fully understood yet. Despite cold-induced FGF21 expression and increased circulating levels in some studies, which co-occur with brown fat thermogenesis, recent studies in cold-acclimated mice demonstrate the dispensability of FGF21 for maintenance of body temperature, thereby questioning FGF21's role for thermogenesis. Here we discuss the evidence either supporting or opposing the role of endogenous FGF21 for thermogenesis based on the current literature. FGF21, secreted by brown fat or liver, is likely not required for energy homeostasis in the cold, but the nutritional conditions could modulate the interaction between FGF21, energy metabolism, and thermoregulation.
Assuntos
Regulação da Temperatura Corporal , Fatores de Crescimento de Fibroblastos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Temperatura Baixa , Sistema Endócrino/metabolismo , Metabolismo Energético , Humanos , Fígado/metabolismo , Comunicação ParácrinaRESUMO
The gut microbiota plays an important role for the absorption of nutrients and the maintenance of metabolism, potentially impacting the development of human metabolic disorders such as obesity and type 2 diabetes. In this issue of Cell Metabolism, Krisko et al. (2020) demonstrate that the gut microbiota regulates glucose homeostasis solely via hepatic gluconeogenesis and not via thermogenic adipose tissue as suggested previously.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Microbiota , Animais , Glicemia , Homeostase , Humanos , Camundongos , TermogêneseRESUMO
Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1.