The Role of UCP1 in Glucose Homeostasis

The worldwide increase in the epidemic of type 2 diabetes (DM2) presents a serious public health issue. Obesity or increased adiposity is thought to be a major contributor to the pathogenesis of DM2. Recent evidence suggests that converting classic white fat into beige, which is characterized by increased expression of uncoupling protein 1 (UCP1) in the process known as “browning” may have beneficial metabolic effects. In particular, it has been suggested that browning may increase energy expenditure due to the ability of UCP1 dissipate energy as heat, and therefore provide means of achieving negative energy balance and weight loss. However, whether sufficient amounts UCP1 protein are expressed in beige fat to achieve enough thermogenesis to result in weight loss is controversial. Here, based on biochemical considerations, we propose that the primary function of UCP1 in beige fat is not to produce heat, but instead to facilitate de novo lipogenesis (DNL) from glucose and that this is an important mechanism to regulate glucose homeostasis. Consistent with this, adipose tissue DNL has recently been demonstrated to regulate glucose homeostasis in humans and animals. Moreover, the PPARγ agonists, thiazolidinediones (TZDs) which exert powerful glucose-lowering and insulin-sensitizing effects, have been shown to promote adipose tissue DNL and cause browning. We propose that the beneficial effects of TZDs depend on beige fat adipose DNL facilitated by UCP1. Here, using UCP1 KO mice, we will test whether UCP1 is important for adipose tissue DNL in the setting of high-carbohydrate feeding. We will also determine whether UCP1 is required for the beneficial effects of TZDs on glucose homeostasis. These studies will provide fundamental insight into the physiology by which glucose homostasis is regulated leading to new strategies for the treatment of DM2.