RESUMO
When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adolescente , Adulto , Idoso , Animais , Glucose , Humanos , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Niacina/farmacologia , Esterol Esterase/metabolismo , Adulto JovemRESUMO
Growth and differentiation factor 15 (GDF15) has recently emerged as a weight loss and insulin-sensitizing factor. Growing evidence also supports a role for GDF15 as a physiological, exercise-induced stress signal. Here, we tested whether GDF15 is required for the insulin-sensitizing effects of exercise in mice and humans. At baseline, both under a standard nutritional state and high-fat feeding, GDF15 knockout (KO) mice display normal glucose tolerance, systemic insulin sensitivity, maximal speed, and endurance running capacity when compared to wild-type littermates independent of sex. When submitted to a 4-week exercise training program, both lean and obese wild-type and GDF15 KO mice similarly improve their endurance running capacity, glucose tolerance, systemic insulin sensitivity, and peripheral glucose uptake. Insulin-sensitizing effects of exercise training were also unrelated to changes in plasma GDF15 in humans. In summary, we here show that GDF15 is dispensable for the insulin-sensitizing effects of chronic exercise.
Assuntos
Fator 15 de Diferenciação de Crescimento , Resistência à Insulina , Insulina , Camundongos Knockout , Condicionamento Físico Animal , Fator 15 de Diferenciação de Crescimento/metabolismo , Fator 15 de Diferenciação de Crescimento/genética , Animais , Humanos , Masculino , Insulina/metabolismo , Insulina/sangue , Feminino , Camundongos , Camundongos Endogâmicos C57BL , AdultoRESUMO
The 5/6 nephrectomy and adenine-induced nephropathy mouse models have been extensively used to study Chronic Kidney Disease (CKD)-related cachexia. One common caveat of these CKD models is the cross-sectional nature of comparisons made versus controls. We here performed a comprehensive longitudinal assessment of body composition and energy metabolism in both models. The most striking finding is that weight loss is largely driven by reduced food intake which promotes rapid loss of lean and fat mass. However, in both models, mice catch up weight and lean mass a few days after the surgery or when they are switched back to standard chow diet. Muscle force and mass are fully recovered and no sign of cachexia is observed. Our data demonstrate that the time-course of kidney failure and weight loss are unrelated in these common CKD models. These data highlight the need to reconsider the relative contribution of direct and indirect mechanisms to muscle wasting observed in CKD.
Assuntos
Caquexia , Insuficiência Renal Crônica , Animais , Camundongos , Caquexia/complicações , Caquexia/metabolismo , Estudos Transversais , Insuficiência Renal Crônica/complicações , Redução de Peso , Composição Corporal/fisiologiaRESUMO
Impaired glucose metabolism is observed in obesity and type 2 diabetes. Glucose controls gene expression through the transcription factor ChREBP in liver and adipose tissues. Mlxipl encodes 2 isoforms: ChREBPα, the full-length form (translocation into the nucleus is under the control of glucose), and ChREBPß, a constitutively nuclear shorter form. ChREBPß gene expression in white adipose tissue is strongly associated with insulin sensitivity. Here, we investigated the consequences of ChREBPß deficiency on insulin action and energy balance. ChREBPß-deficient male and female C57BL6/J and FVB/N mice were produced using CRISPR/Cas9-mediated gene editing. Unlike global ChREBP deficiency, lack of ChREBPß showed modest effects on gene expression in adipose tissues and the liver, with variations chiefly observed in brown adipose tissue. In mice fed chow and 2 types of high-fat diets, lack of ChREBPß had moderate effects on body composition and insulin sensitivity. At thermoneutrality, ChREBPß deficiency did not prevent the whitening of brown adipose tissue previously reported in total ChREBP-KO mice. These findings revealed that ChREBPß is dispensable for metabolic adaptations to nutritional and thermic challenges.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Glicemia/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/genética , Metabolismo Energético/genética , Regulação da Expressão Gênica , RNA/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/biossíntese , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Atrial natriuretic peptide (ANP) is a cardiac hormone controlling blood volume and pressure in mammals. It is still unclear whether ANP controls cold-induced thermogenesis in vivo. Here, we show that acute cold exposure induces cardiac ANP secretion in mice and humans. Genetic inactivation of ANP promotes cold intolerance and suppresses half of cold-induced brown adipose tissue (BAT) activation in mice. While white adipocytes are resistant to ANP-mediated lipolysis at thermoneutral temperature in mice, cold exposure renders white adipocytes fully responsive to ANP to activate lipolysis and a thermogenic program, a physiological response that is dramatically suppressed in ANP null mice. ANP deficiency also blunts liver triglycerides and glycogen metabolism, thus impairing fuel availability for BAT thermogenesis. ANP directly increases mitochondrial uncoupling and thermogenic gene expression in human white and brown adipocytes. Together, these results indicate that ANP is a major physiological trigger of BAT thermogenesis upon cold exposure in mammals.
Assuntos
Fator Natriurético Atrial/metabolismo , Termogênese/fisiologia , Animais , Humanos , Masculino , Camundongos , Camundongos KnockoutRESUMO
Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPß, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.
Assuntos
Adipócitos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Resistência à Insulina , Insulina/metabolismo , Esterol Esterase/metabolismo , Tecido Adiposo/metabolismo , Animais , Biomarcadores , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Expressão Gênica , Glucose/metabolismo , Resistência à Insulina/genética , Fluidez de Membrana/genética , Camundongos , Camundongos Transgênicos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Transdução de SinaisRESUMO
Fibroblast growth factor 1 (FGF-1) is a powerful angiogenic factor whose gene structure contains four promoters, giving rise to a process of alternative splicing resulting in four mRNAs with alternative 5' untranslated regions (5' UTRs). Here we have identified, by using double luciferase bicistronic vectors, the presence of internal ribosome entry sites (IRESs) in the human FGF-1 5' UTRs, particularly in leaders A and C, with distinct activities in mammalian cells. DNA electrotransfer in mouse muscle revealed that the IRES present in the FGF-1 leader A has a high activity in vivo. We have developed a new regulatable TET OFF bicistronic system, which allowed us to rule out the possibility of any cryptic promoter in the FGF-1 leaders. FGF-1 IRESs A and C, which were mapped in fragments of 118 and 103 nucleotides, respectively, are flexible in regard to the position of the initiation codon, making them interesting from a biotechnological point of view. Furthermore, we show that FGF-1 IRESs A of murine and human origins show similar IRES activity profiles. Enzymatic and chemical probing of the FGF-1 IRES A RNA revealed a structural domain conserved among mammals at both the nucleotide sequence and RNA structure levels. The functional role of this structural motif has been demonstrated by point mutagenesis, including compensatory mutations. These data favor an important role of IRESs in the control of FGF-1 expression and provide a new IRES structural motif that could help IRES prediction in 5' UTR databases.
Assuntos
Regiões 5' não Traduzidas , Processamento Alternativo , Fator 1 de Crescimento de Fibroblastos/genética , Conformação de Ácido Nucleico , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Ribossomos/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Técnicas de Transferência de Genes , Genes/genética , Vetores Genéticos , Humanos , Camundongos , Dados de Sequência Molecular , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Mutagênese Sítio-Dirigida , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Alinhamento de SequênciaRESUMO
Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFß1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.