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. 2014 Jun 12;3(6):608-18.
doi: 10.1016/j.molmet.2014.06.001. eCollection 2014 Sep.

Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity

João A B Pedroso  1 , Daniella C Buonfiglio  1 , Lais I Cardinali  1 , Isadora C Furigo  1 , Angela M Ramos-Lobo  1 , Julio Tirapegui  2 , Carol F Elias  3 , Jose Donato Jr  1
Affiliations

Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity

João A B Pedroso et al. Mol Metab. .

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.

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.

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Figures

Figure 1
Figure 1
Neuronal deletion of SOCS3 partially prevented the accumulation of body fat and improved the glucose homeostasis of mice fed the HFD. Body weight (A), cumulative weight gain (B), food intake (C), serum leptin (D), adiposity (E), GTT (F) and ITT (G) of mice consuming HFD. A separate group was maintained on a low-fat regular rodent diet (H). *p < 0.05 compared to the control group.
Figure 2
Figure 2
The Nestin-Cre transgene reduces body weight and affects the adiposity independent of inducing genetic recombination. Body weight (A) and adiposity (B) of mice carrying the Nestin-Cre transgene and their respective littermate wild-type mice. Mice carrying the LepR-Cre allele did not show any differences in body weight (C) and body composition (D) compared to littermate wild-type mice. *p < 0.05 compared to the wild-type group.
Figure 3
Figure 3
Inactivation of SOCS3 in LepR-expressing cells increases leptin sensitivity of mice exposed to HFD. Changes in hypothalamic SOCS3 expression after acute leptin injection (A) and in diet-induced obese mice (B). Effects of chronic leptin treatment reduced on food intake (C–D) and weight gain (E–F). *p < 0.05 compared to the control group.
Figure 4
Figure 4
Inactivation of SOCS3 in LepR-expressing cells did not prevent the obesity induced by HFD. Three independent cohorts of LepR SOCS3 KO and control mice (A–C) were studied to determine the possible changes in body weight, weight gain and food intake caused by a HFD.
Figure 5
Figure 5
LepR SOCS3 KO mice did not show significant differences in the adiposity (A) and leptin levels (B) compared to control animals consuming HFD.
Figure 6
Figure 6
Hypothalamic mRNA expression of genes involved with leptin resistance and energy balance regulation. *p < 0.05 compared to the control group.
Figure 7
Figure 7
LepR SOCS3 KO mice are protected from insulin resistance induced by HFD. Levels of postprandial (A) and overnight fasted (B) glucose, serum insulin (C), serum glucagon (D), GTT (E) and ITT (F) in mice consuming HFD. Activation of the insulin intracellular pathway in the liver (G) and gastrocnemius/soleus muscle (H). *p < 0.05 compared to the control group. #p < 0.05 compared to the respective saline-treated group.
Figure 8
Figure 8
Deletion of SOCS3 from LepR-expressing cells increased hypothalamic expression of Katp channel subunits and c-Fos expression in POMC neurons. Hypothalamic gene expression (A) and c-Fos immunoreactivity in several brain areas (B). Photomicrographs that show the c-Fos expression in the ARH of control (C) and LepR SOCS3 KO mice (D). Photomicrographs that show the co-expression between c-Fos (black nucleus) and β-endorphin (brown cytoplasm) in the ARH of control (E) and LepR SOCS3 KO mice (F). Notice that double-labeled neurons are virtually absent in the ARH of control mice (E), but are abundantly found in the ARH of LepR SOCS3 KO mice (F). *p < 0.05 compared to the control group. Abbreviations: 3v, third ventricle; ME, median eminence. Scale bar = 50 μm.
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