Hoehn, Kyle L.
Assistant Professor, Pharmacology
- PhD, Colorado State University
Investigating the origin of insulin resistance in skeletal muscle and adipose tissue
Obesity is highly associated with metabolic diseases including type 2 diabetes, cardiovascular disease, and some forms of cancer; including endometrial and liver cancers. A common physiologic signature of patients with these diseases is an impaired response to normal concentrations of insulin. The molecular mechanism (or mechanisms) that drive insulin resistance in these individuals is unclear; however the resultant hyperglycemia, hyperinsulinemia, and hyperlipidemia has pathogenic and prognostic significance for disease initiation and progression. Our lab focuses on the etiology of insulin resistance and the mechanisms whereby the altered nutritional milieu with obesity predispositions to cancer, diabetes, and vascular disease.
We have developed a diverse range of insulin resistance models in our lab; these include rodent models of diet-induced obesity, and cultured muscle and fat cell models of hyperlipidemia, inflammation, oxidative stress, steroids, and hyperinsulinemia. By using minimal insults required to achieve insulin resistance and cross-comparing these models we have revealed widespread roles for mitochondria-derived reactive oxygen species (ROS) and lipid metabolites including sphingolipids. Our focus is to define how mitochondria-derived ROS antagonize the insulin action pathway and to determine the relationship between sphingolipids and mitochondrial ROS in the context of insulin action. Identifying new pathways that drive insulin resistance will provide novel inroads for therapeutic intervention in diabetes, vascular disease, and cancer.
A second focus of the lab is to determine how obesity drives cancer initiation and progression. Approximately 20% of cancers in the US are directly linked to obesity. Our lab investigates the role of fat metabolism in cancer cell growth and proliferation. Specifically, we investigate two lipid metabolic pathways in cancer cells; fatty acid oxidation (FAO) and de novo lipogenesis (DNL). Our current objective is to pharmacologically and genetically interrupt these lipid metabolic pathways to block rapid cellular proliferation in cancerous cells, while sparing normal cells and tissues.