title: Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice.
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.
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: João A B
authors.initials: JA
authors.lastname: Pedroso
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Silveira
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Leandro B
authors.initials: LB
authors.lastname: Lima
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Isadora C
authors.initials: IC
authors.lastname: Furigo
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Thais T
authors.initials: TT
authors.lastname: Zampieri
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Ramos-Lobo
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Daniella C
authors.initials: DC
authors.lastname: Buonfiglio
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Pryscila D S
authors.initials: PD
authors.lastname: Teixeira
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Frazão
authors.affiliation: Department of Physiology and Biophysics (J.A.B.P., L.B.L., I.C.F., T.T.Z., A.M.R.-L., D.C.B., P.D.S.T., J.D.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000 Brazil; and Department of Anatomy (M.A.S., R.F.), Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 Brazil.
authors.forename: Jose
authors.initials: J
authors.lastname: Donato
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D005215:Fasting; D005260:Female; D006963:Hyperphagia / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D020738:Leptin; D016760:Proto-Oncogene Proteins c-fos; D054411:Receptors, Leptin; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein