Abstract 021: Role of Central Nervous System Suppressor of Cytokine Signaling 3 (socs3) in Regulating Metabolic and Cardiovascular Function in Obesity

Abstract

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, is upregulated in obesity and may contribute to development of leptin resistance. We determined whether deletion of SOCS3 in the entire central nervous system (CNS) would protect mice from adverse metabolic and cardiovascular effects of a high fat diet (HFD). SOCS3 flox/flox /Nestin-cre mice were generated by breeding SOCS3 flox/flox with Nestin-Cre mice. Male and female mice with CNS deletion of SOCS3 (SOCS3 flox/flox /Nestin-Cre, n=5-10) or control (SOCS3 flox/flox , n=6-10) were fed a HFD plus sucrose from 6 until 22 weeks of age. Mean arterial pressure (MAP) and heart rate (HR) were recorded by telemetry and oxygen consumption (VO 2 ) was monitored by indirect calorimetry in 22-week-old mice. Compared to control mice, SOCS3 flox/flox /Nestin-Cre mice were lighter (male: 34±3 vs. 45±3 and female: 27±1 vs. 37±2 g) and had elevated VO 2 (94±12 vs. 69±6 ml/kg/min) but there were no significant differences in food intake (male: 3.3±0.7 vs. 3.8±0.5 and female: 3.0±0.6 vs. 3.0±0.5 g/day) or plasma glucose (male: 148±8 vs. 198±31 and female 149±12 vs. 164±12 mg/dl). Male SOCS3 flox/flox /Nestin-Cre mice had similar MAP (115±2 vs. 116±1 mmHg) but higher HR (657±3 vs. 592±3 bpm) compared to control mice. However, female SOCS3 flox/flox /Nestin-cre mice had higher MAP (121±1 vs. 108±1 mmHg) and HR (655±2 vs. 606±5 bpm) compared to control mice. No significant differences were observed in glucose tolerance in SOCS3 flox/flox /Nestin-Cre vs. control mice (AUC: 391±36 vs. 429±54 mg/dL x 120 min in males and 459±70 vs. 372±51 mg/dL x 120 min in females). These results indicate that CNS SOCS3 deletion reduced body weight and increased energy expenditure and HR but did not improve glucose tolerance in male or female mice fed a HFD. However, HFD significantly increased BP in female SOCS3 flox/flox /Nestin-Cre mice compared to control mice fed a HFD, suggesting a sex difference in the role of CNS SOCS3 signaling in BP regulation in obesity. (NHLBI PO1HL51971and NIGMS P20GM104357)