Summers, Scott A

Research Interests:

The peptide hormone insulin stimulates the uptake and storage of glucose and other nutrients into adipose tissue and skeletal muscle while simultaneously repressing glucose efflux from the liver. Defects in insulin secretion or action (i.e. insulin resistance) are central features of Diabetes Mellitus and related metabolic diseases. Numerous studies suggest that the accumulation of lipid in tissues not suited for fat storage induces these pathogenic events. Our laboratory investigates the molecular basis of this lipotoxicity.

Our particular focus is on the contribution of ceramides, which are metabolites of saturated fats known to accumulate in obese individuals. The implementation of pharmacological or genetic strategies to inhibit ceramide synthesis in rodents improves insulin sensitivity and prevents diabetes and cardiovascular dysfunction.

Elucidating the regulatory signals controlling rates of ceramide biosynthesis. Ceramide is produced via a ubiquitious de novo synthesis pathway present in all tissues. Rates of ceramide production are not merely regulated by substrate (i.e. fatty acid) availability, but stresses associated with obesity control flux through this biosynthetic pathway. Using both in vitro and in vivo model systems, we are attempting to elucidate the regulatory networks controlling rates of ceramide biosynthesis.

Determining the molecular mechanisms by which ceramide alters insulin sensitivity, pancreatic ß-cell homeostasis, and vascular function. Ceramide modulates insulin signaling in skeletal muscle and the liver, damages pancreatic ß-cells which secrete insulin, and alters vascular reactivity. Despite extensive investigation, a consensus mechanism for the effects of ceramide on these events has not emerged. We are aiming to determine how small changes in cellular ceramide levels have such a profound impact on cellular function and metabolic homeostasis.

Identifying the role of portal ceramides. The liver appears to be a major site of ceramide action. In a rodent model of insulin resistance (i.e. glucocorticoid-treated rodents), ceramide levels are markedly elevated in the portal serum, raising the possibility that liver ceramide derives from extra-hepatic sources. We are studying the hypothesis that ceramide generated in and secreted from visceral white adipose tissue modulates insulin sensitivity and glucose homeostasis in peripheral tissues. Specifically, we theorize that the delivery of ceramide through the portal circulation is a primary mechanism by which adipose tissue communicates energy status or need. To test this theory, we are attempting to identify which tissues produce the pools of ceramide that are most relevant in metabolic disease.

Selected Publications:

Holland, WL and Summers SA. (2008) Sphingolipids in insulin resistance and metabolic disease: New insight from in vivo manipulation of sphingolipid synthesis. Endocrine Reviews 29(4), 381-402

Holland WL, Brozinick JT, Wang L, Hawkins ED, Sargent KM, Liu Y, Narra, K., Hoehn, K. L., Knotts TA, Sieskky, A.., Nelson D. H., Karathanasis S. K., Fontenot G. K., Birnbaum M. J., Summers S. A. (2007) Inhibition of Ceramide Synthesis Ameliorates Glucocorticoid-, Saturated Fat- and Obesity-Induced Insulin Resistance. Cell Metabolism 5(3), 167-79.

Holland WL, Knotts TA, Chavez JA, Hoehn KL, Summers SA. (2007) Lipid mediators of insulin resistance. Nutrition Reviews 65(6), S39-S46

Summers, Scott A. (2006) Ceramides in insulin resistance and lipotoxicity. Progress in Lipid Research 45. 42-72.

Summers, S. A. and Nelson, D. (2005) A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing’s syndrome. Diabetes 54(3):591-602.

Chavez, J. A., Holland, W., Julia Bär, Sandhoff, K. and Summers, S. A. (2005) Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. Journal of Biological Chemistry 280(20), 20148-53.

Safadi-Chamberlain, F., Wang, L. P., Payne, S. G., Lim, C. U., Stratford, S., Chavez, J. A., Fox, M. H., Spiegel, S., and Summers, S. A. (2005) Effect of a membrane-targeted sphingosine kinase 1 on cell proliferation and survival. Biochemical Journal 388(3), 827-834.

Stratford, S., Hoehn, K. L., Liu, F., and Summers, S. A. (2004) Regulation of insulin action by ceramide: Dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. Journal of Biological Chemistry 279(35), 36608-15