Increasing Fat Metabolism: Identification of a New Pathway in Adipose Tissue

Inventors: Marc R. Montminy, Jose E. Heredia, and Ling Qi
Potential Uses: Drug Discovery and Development, Diabetes, Obesity

Novel pathway providing targets and markers for agents that enhance TRB3 activity in adipose tissue

Figure 1. Effect of high-fat diet on weight gain in Transgenic Mice with TRB3 (Tg) and control littermates (wt) over a 5-week period (n 0 8) (n, sample size for each cohort). *P G 0.05, **P G 0.01. Tg mice with TRB3 have significantly less weight gain.

During fasting, adipose lipid stores are mobilized to provide fatty acids for use as a metabolic energy source. We have recently discovered that the enzyme Tribbles 3 (TRB3), a pseudo kinase, is a key component in a previously unknown pathway for the mobilization of adipose lipids during fasting. Researchers have known about the pathway for mobilization of lipid stores that involves inactivating acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis, via a phosphorylation-dependence mechanism. This new pathway complements that mobilization.

TRB3 promotes lipid metabolism via protein-protein interactions with E3 ubiquitin ligase Constitutive Photomorphogenic Protein 1 (COP1) and ACC. TRB3 enhanced the COP1-dependent ubiquitination (and phosphorylation-independent) inactivation of ACC. In the process of stimulating lipid metabolism in adipose, TRB3 is itself phosphorylated and ubiquinated. Advantageously, activation of this TRB3 dependent pathway does not promote insulin resistance in vivo, and transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation (see Figure 1). This newly discovered TRB3-dependent pathway provides targets and markers for the identification of agents that enhance TRB3 activity and which, in turn, could lead to potential candidates for therapeutics for mobilizing adipose fat stores and in the treatment of metabolic disorders such as obesity.