270-LB: Amelioration of Hepatic Insulin Resistance by Brown Adipocyte Secretion

Abstract

Insulin resistance (IR) is a hallmark of T2D. In the IR state, insulin fails to inhibit hepatic glucose production yet promotes lipogenesis. Although thiazolidinediones can partially reinstate insulin sensitivity, there are concerns about long-term usage. Recent studies have shown positive effects of paracrine signaling from BAT transplant on metabolic homeostasis. Transplant of embryonic BAT into diabetic mice can improve glucose tolerance. However, the mechanisms are unclear. In this study, we show that brown adipocyte secretions can partially resolve hepatic IR. We cultured primary hepatocytes in a microfluidic organ-on-chip device. IR was induced by cytokine exposure and the cells were treated with brown adipocyte secretions among other controls. The group treated with brown adipocytes had restored insulin sensitivity. This was verified by an increased Akt phosphorylation (Figure 1), lowered glucose production, increased glucose uptake, and increased glycogen synthesis. We finally confirmed that genes important for glucose production (G6pc, PEPCK) and lipogenesis (SREBP1) were downregulated in the treated cells. We will present results from ongoing mechanistic studies. Our data imply that brown adipocyte secretions contain factors that regulate hepatic insulin sensitivity and could be potential targets for drug development. Disclosure A. Bhushan: None. N. Tanataweethum: None. C. Lee: None. F. Zhong: None. A. Trang: None. A. Budiman: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK095984NIH, P30DK020595)