Abstract 077: Role of Suppressor of Cytokines Signaling 3 (SOCS3) in POMC Neurons in Regulating Metabolic and Cardiovascular Functions in Dietary-Induced Obesity

Abstract

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, may contribute to the development of obesity-induced leptin resistance. Previously, we showed that activation of proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on blood pressure (BP) and glucose regulation. However, the role of SOCS3 in POMC neurons in regulating metabolic and cardiovascular functions in obesity is still unclear. To address this question, we used male and female mice with SOCS3 deleted only in POMC neurons (SOCS3 flox/flox -POMC/cre) and flox control (SOCS3 flox/flox ) mice. After weaning, mice were fed normal chow until 20 wks of age; then glucose tolerance tests (GTT) were performed and telemetry probes were implanted to measure mean arterial pressure (MAP) 24-hrs/day. We found that at 23 wks of age, both male and female SOCS3 flox/flox -POMC/cre mice weighed less than control mice (32±1 vs 37±2 g in male and 25±1 vs 27±1 g in female, n=9-11, p <0.05), but had similar daily food intake (3.5±0.2 g in male and 3.3±0.1 g in female) and MAP (114±1 vs 115±2 mmHg). Only male SOCS3 flox/flox -POMC/cre mice exhibited improved glucose tolerance (AUC: 1059±52 vs 1283±54 mg/dL x 120 min, n=7-10, p <0.05) compared to controls. From 23 wks, mice were switched to a high fat diet (45%, HFD) for 6 wks. After HFD feeding, both male and female SOCS3 flox/flox -POMC/cre mice had slightly reduced food intake (3.2±0.1 vs 3.5±0.2 g in male and 2.7±0.1 vs 3.0±0.2 g in female) and a trend toward lower body weight gain (10±1 vs 12±1 g in male and 4±1 vs 6±1 g in female), although the differences were not significant compared to controls. However, male and female SOCS3 flox/flox -POMC/cre mice fed a HFD had significantly greater MAP increase (7±1 vs 1±1 mmHg, n=13-16, p <0.05) and an enhanced BP response to acute air-jet stress (AUC: 109±9 vs 74±12 mmHg x 5min, n=8-13, p <0.05). After HFD, glucose tolerance was impaired in all groups of mice compared to the baseline at 20 wks, but there were no differences between SOCS3 flox/flox -POMC/cre and controls. These results suggest that deletion of SOCS3 in POMC neurons amplifies the BP response to a HFD and to acute stress, but has minimal effects on metabolic functions to HFD. (NHLBI PO1HL51971, NIGMS P20GM104357, AHA 14POST18160019)