Saltiel Lab Research

There is little doubt that we are in the midst of a worldwide epidemic of diabetes and obesity.

These related diseases arise from dysregulation of energy metabolism, and making progress towards new treatments requires a better understanding of the underlying molecular mechanisms. To this end, the Saltiel lab investigates the molecular events involved in the regulation of nutrient uptake and storage by insulin, and regulation of mobilization and utilization by catecholamines and glucagon. We seek to understand how energy metabolism is controlled in fat and liver cells, and how these cells talk to each other, with special attention to mechanisms underlying the specificity of the actions of hormones, and the inflammatory links between obesity and diabetes. 

Signaling Pathways in Insulin Action

Insulin-stimulated glucose transport is mediated by the glucose transporter Glut4, which translocates from intracellular compartments to the plasma membrane of muscle and fat cells in response to insulin. We discovered a novel signaling cascade initiated by the phosphorylation of the protooncogene c-Cbl, recruited to the receptor by the adapter protein SH2B2, and anchored to lipid raft microdomains by a multifunctional protein called CAP. And results in activation of the small GTPase TC10. TC10 interacts with different effectors, including the​ exocyst component Exo70.

The exocyst is an octameric complex first identified in yeast as a tethering site for targeted exocytosis. We discovered that this complex plays a key role in the regulation of glucose transport, targeting Glut4 vesicles to sites of docking and fusion in adipocytes. The assembly and recognition of the exocyst by Glut4 vesicles is controlled by distinct G proteins activated by a different process. The activation of TC10 recruits the exocyst to the plasma membrane, while activation of the vesicular G protein RalA is required for exocyst recognition. RalA is a target of insulin action, activated via phosphorylation of its cognate GAP protein that was cloned and characterized by our lab. We are focusing on upstream and downstream pathways in the control of RalA in vitro and in knockout mouse models. 

Hormonal Regulation of Glycogen Metabolism

Defects in the regulation of non-oxidative glucose metabolism by insulin is a primary lesion in insulin resistance. In peripheral tissues, insulin modulates glycogen accumulation through a coordinate increase in glucose transport and regulation of glycogen metabolizing enzymes, while in liver insulin blocks glucose output by inhibiting gluconeogenesis, promoting glycogenesis and blocking glycogenolysis. We identified PTG as a protein phosphatase-scaffolding molecule that localizes exclusively to glycogen particles and promotes the dephosphorylation of glycogen synthase and phosphorylase. Studies on this protein have led to a new link between glycogen metabolism and thermogenesis in adipocytes, in which glycogen turnover is dynamically regulated to safeguard induction of ATP uncoupling in beige fat. Glycogen also plays a specific regulatory role in liver, controlling gluconeogenesis via a newly discovered regulatory pathway.

Inflammatory Links between Obesity and Diabetes

Obesity induces a state of chronic low-grade inflammation that contributes to the development of metabolic syndrome and diabetes. The inflammatory changes in obesity include monocyte activation, increased circulating inflammatory factors, and inflammation in fat and liver tissue. A key component of the inflammatory response to obesity is the infiltration of macrophages. Adipose tissue macrophages (ATMs) are a source of inflammatory cytokines that alter adipocyte insulin sensitivity and are required for the development of diabetes in obese mice. We have performed detailed characterization of the properties of ATMs isolated from lean and obese mice using a model of high fat diet feeding. These studies have shown that obesity leads to significant alterations in the inflammatory properties of ATMs and have revealed mechanisms by which activated macrophages impair fat cell function. We recently uncovered a crucial role for the protein kinases TBK1 and IKKe in this process. These kinases modulate energy homeostasis in fat and liver by phosphorylating and regulating the activities of group of proteins that are involved in energy expenditure, including AMPK and cAMP phosphodiesterase. These studies have also led us to exploring the role of obesity and inflammation in controlling sensitivity of fat and liver cells to other hormones, especially catecholamines, and to dissect the signaling pathways used by catecholamines to regulate thermogenesis in adipocytes. Studies are underway to identify the early molecular triggers in obesity-dependent inflammation.

Understanding the pathophysiology of MAFLD and MASH 

Among the many complications of obesity are metabolic fatty liver disease (MAFLD) and metabolic associated steatohepatitis (MASH), characterized by hepatic steatosis with inflammation and liver damage. MASH has become one of the leading causes of liver transplant and liver-associated death. Despite years of attention, the underlying mechanisms remain unresolved, particularly regarding the control of hepatocellular death, and its relation to systemic metabolic homeostasis. We have explored the links between obesity, MAFLD and MASH, and have focused on the metabolic regulators of metabolism and their control of apoptotic enzymes. Our studies indicate that the energy sensor AMPK is dramatically reduced in obese liver, due to a combination of hyperinsulinemia resulting from insulin resistance and inflammation. Reduced AMPK activity results in the release of the apoptotic enzyme caspase 6, which turns on an irreversible cascade to produce hepatocellular death and liver fibrosis. We are studying the molecular mechanisms involved in this process and searching for inhibitors of this key enzyme.