RESUMO
Many proinflammatory cytokines, such as leptin, play key roles in dynamic regulation of energy expenditure and food intake. The present work tested a role for the proinflammatory cytokine GM-CSF. Central but not peripheral administration of GM-CSF to adult rats significantly decreased food intake and body weight for at least 48 hours. Similar results were observed following central administration of GM-CSF in mice. GM-CSF receptor immunoreactivity was found on neurons within the paraventricular and arcuate nuclei of the hypothalamus. GM-CSF-deficient (GM-/-) mice weighed more and had significantly higher total body fat than wild-type (GM+/+) mice. Energy expenditure in GM-/- mice was decreased compared with that in GM+/+ mice. Taken together, these findings demonstrate that GM-CSF signaling in the CNS can regulate energy homeostasis.
Assuntos
Sistema Nervoso Central/fisiologia , Ingestão de Alimentos/fisiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Redução de Peso/fisiologia , Tecido Adiposo/metabolismo , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Relação Dose-Resposta a Droga , Jejum/fisiologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/deficiência , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Obesidade/fisiopatologia , Ratos , Ratos Long-Evans , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/biossíntese , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Proteínas Recombinantes/genéticaRESUMO
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine that has a central action to reduce food intake and body weight. Consistent with this, GM-CSF knockout mice are more obese and hyperphagic than wild-type mice. However, in lung, GM-CSF is an important determinant of macrophage infiltration. Consequently, we sought to determine if GM-CSF might contribute to adipose tissue macrophage accumulation, insulin resistance, and low-grade inflammation that occurs when animals gain weight on a high-fat diet (HFD). We therefore determined how targeted genetic disruption of GM-CSF can affect adipose tissue macrophage and cytokine gene expression as well as glucose homeostasis by performing hyperinsulinemic-euglycemic clamps. The number of macrophages and CCR2 gene expression in adipose tissue of GM-CSF knockout mice was decreased relative to those in wild-type mice, and the adipocyte size of mesenteric fat was increased in GM-CSF knockout mice on a HFD compared with wild-type mice. The level of mRNA of the proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha, and macrophage inflammatory protein-1alpha was significantly lower in mesenteric fat of GM-CSF knockout mice on the HFD than in wild-type mice. Using the hyperinsulinemic-euglycemic clamp technique, GM-CSF knockout mice had greater overall insulin sensitivity. This increase was due to enhanced peripheral uptake and utilization of glucose rather than to increased hepatic insulin sensitivity. Collectively, the data suggest that the GM-CSF knockout mutation ameliorates peripheral insulin resistance in spite of increased adiposity by reducing inflammation in adipose tissue in response to a HFD.
Assuntos
Tecido Adiposo Branco/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Inflamação/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Animais , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Peso Corporal/fisiologia , Contagem de Células , Quimiocina CCL2/genética , Quimiocina CCL3/genética , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Expressão Gênica/efeitos dos fármacos , Técnica Clamp de Glucose , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Inflamação/patologia , Insulina/sangue , Interleucina-1beta/genética , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Mesentério/efeitos dos fármacos , Mesentério/metabolismo , Mesentério/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genéticaRESUMO
Ghrelin is a gut peptide that stimulates food intake and increases body fat mass when administered centrally or peripherally. In this study, ghrelin was overexpressed in neurons using the neuron-specific enolase (NSE) promoter sequences and mouse ghrelin cDNA (NSE-Ghr). Ghrelin expression in NSE-Ghr brain tissues was increased compared with wild-type mice. Ghrelin expression was also increased to a much smaller extent in liver of these mice, but mRNA levels in stomach or duodenum did not differ from wild-type mice. Body weight and composition was analyzed in two lines of NSE-Ghr mice, one line with increased circulating bioactive ghrelin (L43) and one line without (L73). No increases in body weight, food intake, or fat mass were found. Energy expenditure was measured in L43 mice and did not differ from wild-type controls, whereas locomotor activity was increased in NSE-Ghr mice. Young NSE-Ghr mice had normal glucose tolerance; however, L43 NSE-Ghr mice, but not L73 mice, developed glucose intolerance at 32 wk of age. Despite the impaired glucose tolerance in L43 mice, insulin levels did not differ from those of wild-type mice. These findings suggest a role for ghrelin in age-associated impairments of glucose homeostasis.
Assuntos
Envelhecimento/fisiologia , Grelina/sangue , Grelina/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Tecido Adiposo/fisiologia , Animais , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Duodeno/fisiologia , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Expressão Gênica/fisiologia , Fígado/fisiologia , Camundongos , Camundongos Transgênicos , Obesidade/metabolismo , Obesidade/fisiopatologia , RNA Mensageiro/metabolismo , Estômago/fisiologiaRESUMO
Signal transducers and activators of transcription (STATs) are critical components of cytokine signaling pathways. STAT5A and STAT5B (STAT5), the most promiscuous members of this family, are highly expressed in specific populations of hypothalamic neurons in regions known to mediate the actions of cytokines in the regulation of energy balance. To test the hypothesis that STAT5 signaling is essential to energy homeostasis, we used Cre-mediated recombination to delete the Stat5 locus in the CNS. Mutant males and females developed severe obesity with hyperphagia, impaired thermal regulation in response to cold, hyperleptinemia and insulin resistance. Furthermore, central administration of GM-CSF mediated the nuclear accumulation of STAT5 in hypothalamic neurons and reduced food intake in control but not in mutant mice. These results demonstrate that STAT5 mediates energy homeostasis in response to endogenous cytokines such as GM-CSF.
Assuntos
Sistema Nervoso Central/metabolismo , Metabolismo Energético , Obesidade/etiologia , Hipófise/metabolismo , Fator de Transcrição STAT5/fisiologia , Transdução de Sinais , Transporte Ativo do Núcleo Celular , Animais , Citocinas/fisiologia , Feminino , Homeostase , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/metabolismoRESUMO
Rats prone to develop diet-induced obesity (DIO) have reduced central sensitivity to many metabolic and hormonal signals involved in energy homeostasis. High-fat diets produce similar defects in diet-resistant (DR) rats. To test the hypothesis that genotype and diet exposure would similarly affect central insulin signaling, we assessed the anorectic effects of 8 mU third ventricular (iv3t) insulin before and after 4 wk intake of a 31% fat, high-energy (HE) diet intake in outbred (OutB) rats. Rats were retrospectively designated as DR or DIO by their low or high weight gains on HE diet. Before the HE diet, iv3t insulin reduced 4-h and 24-h chow intake by 53% and 69% in DR rats but by only 17% and 27% in DIO rats, respectively. Also, the anorectic response to iv3t insulin in OutB rats was inversely correlated (r = 0.72, P = 0.002) with subsequent 4-wk weight gain on the HE diet. Similarly, in selectively bred (SB) chow-fed DR rats, 8 mU iv3t insulin reduced 4-h and 24-h intake by 21% and 22%, respectively, but had no significant effect in SB DIO rats. Four-week HE diet intake reduced 4-h and 24-h insulin-induced anorexia by 45% in OutB DR rats and completely abolished it in SB DR rats. Reduced insulin responsiveness was unassociated with differences in arcuate nucleus insulin receptor mRNA expression between DIO and DR rats or between rats fed chow or HE diet. These data suggest that DIO rats have a preexisting reduction in central insulin signaling, which might contribute to their becoming obese on the HE diet. However, since the HE diet reduced central insulin sensitivity in DR rats but did not make them obese, it is likely that other brain areas are involved in insulin's anorectic action or that other pathways contribute to the development and maintenance of obesity.