The role of DHRS9 in diet-induced obesity and diabetes

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Texas Woman's University $133,175 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate the role of DHRS9 in diet-induced obesity and diabetes.

The research project will define how DHRS9 modulates insulin sensitivity under high-fat diet conditions across sexes and determine whether retinoid or specialized pro-resolving mediator (SPM) metabolism represents the dominant DHRS9-regulated target. The principal investigator will feed wild-type and DHRS9 knockout mice on high-fat vitamin-A-defined diets and rescue these mice with all-trans retinoic acid or SPMs. The work will characterize insulin signaling and metabolic pathways alongside vitamin A metabolites and SPMs to elucidate the crosstalk between vitamin A metabolism and omega-3 fatty acid-derived SPMs in obesity and insulin resistance pathology.

Work is performed in Texas. The project period extends from September 1, 2026, through May 31, 2030. This is a project grant, the standard assistance type for NIH research awards to institutions and individuals proposing to establish, expand, and improve research activities in health sciences.

Abstract

Obesity-associated insulin resistance remains inadequately studied. Both vitamin deficiency and overconsumption lead to obesity and insulin resistance. Specialized pro-resolving mediators (spms) originate from omega-3 fatty acids and serve to terminate inflammation and insulin resistance. DHRS9 plays dual role in vitamin a metabolism and the inactivation of spms in skin, lungs, and trachea. The role of DHRS9 in diet-induced obesity and diabetes is not explored. The objectives are to define how DHRS9 modulates insulin sensitivity under high-FAT diet (HFD) conditions across sexes and determine whether retinoid or spms metabolism is the dominant DHRS9-regulated target. Our central hypothesis is that DHRS9 promotes insulin resistance by distorting local retinoic acid (RA) tone and/or dampening pro-resolving lipid signals; loss of DHRS9 preserves insulin action, and metabolite rescue will reveal pathway dominance. The specific aims are to: 1) identify the role of DHRS9 in diet-induced obesity and diabetes; and 2) establish whether RA or oxylipins can rescue the differential response to HFD seen in DHRS9 knockout mice. The approach is to feed wild-type and DHRS9 knockout mice on HFD vitamin-a-defined AIN93 diets. We will also rescue these mice with all-trans RA or spms. Phenotypically, we will monitor their physiological profiles in diet-induced obesity and diabetes. Mechanistically, we will characterize insulin signaling and metabolic pathways, as well as vitamin a metabolites and spms. Elucidating the role of DHRS9 in diet-induced obesity and diabetes is significant because IT will identify the roles of vitamin a and omega-3 fatty acids in diet-induced obesity and diabetes, addressing a fundamental GAP in the crosstalk between vitamin a metabolism and omega-3 fatty acid derived spms, while expanding research capacity at a sure-eligible institution. The proposed research is innovative because IT reframes DHRS9 as a bifunctional controller of RA-spms biology and deploying a mechanistic metabolite-rescue strategy integrated with time-resolved, SEX-aware physiology and quantitative mediator profiling. IT will provide reference to evidence-based interventions-dietary vitamin a modulation and DHRS9-targeted therapeutics-to treat diet- induced obesity and diabetes.