1538-P: Brain TGFß Regulates Glucose Tolerance in Male Mice with Metabolic Syndrome

Abstract

Hypothalamic inflammation contributes to insulin resistance and obesity. Transforming growth factor beta (TGFβ) is among the inflammatory mediators inducing hypothalamic inflammation. In this study, we investigated the role of brain TGFβ on metabolic function. We hypothesized that TGFβ in the brain promotes insulin resistance and reduces glucose tolerance in diabetic and obese mice. C57BL/J male mice were fed either hypercaloric diet (HCD, 52% fat) or regular diet (RD) from weaning. At 3 months age, intraperitoneal glucose tolerance test (GTT), insulin tolerance test (ITT) and weight confirmed the acquisition of metabolic syndrome. Hypothalamic protein expression was assessed for TGFβ receptor 2, phosphorylated SMAD3, SMAD6 and SMAD7, as downstream signal transducer proteins for TGFβ. Compared to RD male mice (n=6), mice on HCD (n=6) showed glucose intolerance (AUC; 60587 ±2460 vs. 30802±1923, p<0.0001), insulin intolerance (AUC; Mean±SEM; 19025836.0 vs.11436±1087, p=0.02) and weight gain (33.67±2.028 vs. 26.89±0.4231 g). HCD mice also exhibited increased protein levels of TGFβR2 (normalized to total protein, Fold Change (FC)±SEM to RD group; 3.54±0.3, p<0.0001), pSMAD3 (FC 2±0.5, p=0.04) while inhibitors for TGFβ signaling such as SMAD6 and SMAD7, were downregulated (FC 0.7±0.1, p=0.03 and 0.8±0.04, p=0.03, respectively). To understand the role of brain TGFβ on metabolic regulation, 3 months HCD mice were subjected to intracerebroventricular (ICV) infusion with either TGFβ neutralizing antibody (nAb, n=4) or IgG control antibody (n=4) using subcutaneous osmotic pumps connected to ICV cannula for 2 weeks. GTT was measured after 2-week infusion. Treatment with TGFβ nAb resulted in lower fasting blood glucose compared to before treatment (166.1 ±6.878 vs. 229.9 ±3.923 mg/dL) and at 120 min time point (229.9 ±28.69 vs. 382.2 ±24.33 mg/dL). In conclusion, brain TGFβ plays a key role in regulating glucose metabolism probably through inflammation-induced insulin resistance. Disclosure M.Elgazzaz: None. K.Miao: None. A.R.Nuzzo: None. L.Restivo: None. K.Moles: None. E.D.Lazartigues: None. Funding American Diabetes Association (1-19-IBS-291 to E.D.L.)