343-OR: Identifying Nogo-B Receptor as a Resilience Factor in Preventing Obesity-Associated Type 2 Diabetes

Obesity is a well-known risk factor for type 2 diabetes (T2D), with over 90% of T2D patients being overweight or obese. However, only approximately 30% of obese individuals develop T2D, suggesting the existence of resilience factors in non-T2D obese individuals that protect against obesity-related T2D. Our research aimed to identify these protective factors by comparing gene expression profiles between obese T2D patients and obese individuals without T2D. Our findings suggest that the Nogo-B receptor (NgBR) may be a key resilience factor in preventing obesity-induced T2D. We observed that obesity-induced loss of NgBR in the liver disrupts the regulation of hepatic gluconeogenesis and insulin sensitivity. This was further supported by decreased NgBR expression in the livers of diabetic mice and T2D obese patients, compared to non-T2D obese and lean subjects. NgBR hepatocyte-specific knockout mice exhibited a moderate increase in blood glucose levels, which was significantly augmented by high-fat diet (HFD) feeding to T2D levels. Our data demonstrated that NgBR plays a crucial, previously unrecognized role in maintaining AMPK activation. NgBR binds to the farnesylated form of liver kinase B1 (LKB1), a key regulator of AMPK. The depletion of NgBR in hepatocytes disrupts the localization of LKB1 in the plasma membrane, impairing AMPK activation, a critical signal for adiponectin-mediated insulin sensitivity. The loss of NgBR in the obese liver disrupts adiponectin-dependent regulation of hepatic gluconeogenesis and insulin sensitivity. NgBR hepatocyte-specific knockout mice display many prediabetes characteristics and are more susceptible to HFD-induced T2D onset.

In conclusion, our findings indicate that NgBR is a critical resilience factor necessary for maintaining hepatic gluconeogenesis regulation and preventing insulin resistance in obesity-associated T2D.