title: Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity.
abstract: Therapies that improve leptin sensitivity have potential as an alternative treatment approach against obesity and related comorbidities. We investigated the effects of Socs3 gene ablation in different mouse models to understand the role of SOCS3 in the regulation of leptin sensitivity, diet-induced obesity (DIO) and glucose homeostasis. Neuronal deletion of SOCS3 partially prevented DIO and improved glucose homeostasis. Inactivation of SOCS3 only in LepR-expressing cells protected against leptin resistance induced by HFD, but did not prevent DIO. However, inactivation of SOCS3 in LepR-expressing cells protected mice from diet-induced insulin resistance by increasing hypothalamic expression of Katp channel subunits and c-Fos expression in POMC neurons. In summary, the regulation of leptin signaling by SOCS3 orchestrates diet-induced changes on glycemic control. These findings help to understand the molecular mechanisms linking obesity and type 2 diabetes, and highlight the potential of SOCS3 inhibitors as a promising therapeutic approach for the treatment of diabetes.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: João A B
authors.initials: JA
authors.lastname: Pedroso
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Daniella C
authors.initials: DC
authors.lastname: Buonfiglio
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Lais I
authors.initials: LI
authors.lastname: Cardinali
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Isadora C
authors.initials: IC
authors.lastname: Furigo
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Ramos-Lobo
authors.affiliation: Department of Food Science and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Julio
authors.initials: J
authors.lastname: Tirapegui
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA ; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA ; Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Carol F
authors.initials: CF
authors.lastname: Elias
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Jose
authors.initials: J
authors.lastname: Donato
keywords: AP, area postrema; ARH, arcuate nucleus of the hypothalamus; DIO, diet-induced obesity; DMV, dorsal motor nucleus of the vagus; GTT, glucose tolerance test; HFD, high-fat diet; High-fat diet; Hypothalamus; ITT, insulin tolerance test; KO, knockout; LepR, leptin receptor; Leptin resistance; NTS, nucleus of the solitary tract; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; POMC; POMC, proopiomelanocortin; PTPs, protein-tyrosine phosphatases; SOCS3, suppressor of cytokine signaling-3; Suppressor of cytokine signaling-3; T2DM, type 2 diabetes mellitus; Type 2 diabetes mellitus; VMH, ventromedial nucleus of the hypothalamus