Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice

Author(s)

Pedroso, Joao A. B. ; Silveira, Marina A. ; Lima, Leandro B. ; Furigo, Isadora C. ; Zampieri, Thais T. ; Ramos-Lobo, Angela M. ; Buonfiglio, Daniella C. ; Teixeira, Pryscila D. S. ; Frazao, Renata ; Donato, Jr., Jose

• Document type: Journal article
• Source: Endocrinology; v. 157, n. 10, p. 3901-3914, OCT 2016.
• Web of Science Citations: 9

Abstract

Weight regain frequently follows interventions that reduce body weight, leading to a failure in long-term obesity treatment. Inhibitory proteins of the leptin signaling pathway, such as the suppressor of cytokine signaling 3 (SOCS3), have been studied in conditions that predispose animals to obesity. However, whether SOCS3 modulates postrestriction hyperphagia and weight regain remains unknown. Mice lacking SOCS3 protein specifically in leptin receptor (LepR)-expressing cells (LepR SOCS3 knockout {[}KO]) were generated and studied in fasting and refeeding conditions. LepR SOCS3 KO mice exhibited increased leptin sensitivity in the hypothalamus. Notably, LepR SOCS3 KO males and females showed attenuated food intake and weight regain after 48 hours of fasting. Postrestriction hyperleptinemia was also prevented in LepR SOCS3 KO mice. Next, we studied possible mechanisms and neural circuits involved in the SOCS3 effects. SOCS3 deletion did not prevent fasting-or refeeding-induced c-Fos expression in the arcuate nucleus of the hypothalamus (ARH) nor fasting-induced increased excitability of ARH LepR-expressing cells. On the other hand, SOCS3 ablation reduced the mRNA levels of hypothalamic orexigenic neuropeptides during fasting (neuropeptide Y, agouti-related protein, orexin, and melanin-concentrating hormone). In summary, our findings suggest that increased leptin sensitivity contributes to the maintenance of a reduced body weight after food deprivation. In addition, the attenuated postrestriction food intake observed in mutant mice was not explained by fasting-induced changes in the activity of ARH neurons but exclusively by a lower transcription of orexigenic neuropeptides during fasting. These results indicate a partial dissociation between the regulation of neuronal activity and gene expression in ARH LepR-expressing cells. (AU)

• FAPESP's process: 13/25032-2 - The role of SOCS3 in the control of hyperphagia, body weight regain and gluconeogenesis after a period of food restriction
• Grantee: João Alfredo Bolivar Pedroso
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/18086-0 - Molecular basis of leptin resistance
• Grantee: Jose Donato Junior
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 14/11752-6 - Study of leptin functions during intrauterine and childhood stages in mice
• Grantee: Angela Maria Ramos Lobo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/12202-4 - Kiss1 neurons biophysical properties modulation by circadian factors
• Grantee: Renata Frazão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/10992-6 - Investigation of metabolic programming through different approaches
• Grantee: Jose Donato Junior
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07908-8 - Precocious puberty in childhood obesity: possible mechanisms and influence of leptin
• Grantee: Renata Frazão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/15517-6 - Involvment of molecular factors in metabolic changes during pregnancy: role of SOCS3
• Grantee: Thais Tessari Zampieri
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/21722-4 - Mechanism of action of bromocriptine and prolactin antagonists in the treatment of Diabetes and Obesity
• Grantee: Isadora Clivatti Furigo
• Support Opportunities: Scholarships in Brazil - Doctorate