Metabolism (Co-Leaders: Richard Bergman and Jerrold Olefsky)

Studies of metabolism encompass a broad range of activities ranging from fundamental basic research in model systems to direct interventional clinical studies at the bedside, and is the largest focus in the DRC. The members in this research base study insulin resistance, the pathophysiology of type 1 and 2 diabetes, obesity, the microbiome, regulatory peptide biology, and understanding of new therapeutics. Highlights include the following.

 

 

  1. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges, by DRC member Panda and others in Cell Metabolism (2014). Panda and colleagues show that time restricted feeding attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration, and stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type 2 diabetes. This manipulation may prevent and treat obesity and metabolic disorders, including type 2 diabetes, hepatic steatosis, and hypercholesterolemia.
  2. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects, by DRC member Saghatelian and others in Cell (2015). Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (PAHFAs) that correlate with insulin sensitivity, and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion, suggesting that these endogenous lipids have the potential to treat type 2 diabetes.
  3. Genomic studies lead to identification of effector transcripts, and the direction of effect. A major goal of genomic studies is to identify the causative gene as this can be the target for new therapies. This goal was advanced by DRC members Chen, Goodarzi, Guo, Rotter and Taylor in two papers in Nature Genetics (2018). In the first of these, coding variant data (the exome chip) was obtained in over 81,000 T2D individuals and 370,000 controls, identifying 40 coding variant association signals. Large scale genome-wide association data was used to fine map the associated variants in their regional context. Compelling evidence was obtained for only 16 signals, and in 13 the coding variants were clearly “false leads.” A second approach is to utilize increasingly large samples, in this case 898,000 European descent individuals (9% T2D cases). Not only were they able to extend the number of T2D loci to 243 (greater than a doubling), with 403 distinct association signals, but substantially improved fine-mapping of causal variants at 51 signals to a single variant (>80% posterior probability of association), and using tissue specific annotations, extend the single variants identified to 73. 18 genes were considered validated therapeutic targets with associations attributable to coding variants.
  4. Adipose tissue-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity, byDRC members Olefsky, Fu and others in Cell (2017). MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Olefsky and colleagues showed that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients. miR-155 is one of the miRNAs overexpressed in obese ATM Exos. Transplantation of WT bone marrow into miR-155KO mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo that regulate cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.