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Aldhehyde Dehydrogenase Family-1 Regulates Female-Specific Visceral Obesity

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Title: Aldhehyde Dehydrogenase Family-1 Regulates Female-Specific Visceral Obesity
Creators: Reichert, Barbara
Advisor: Ziouzenkova, Ouliana
Issue Date: 2010-06
Abstract: Diet and estrogen influence female visceral obesity by poorly understood effector mechanisms. Estrogen regulates the aldehyde dehydrogenase-1 family of enzymes (Aldh1A1, A2, and A3) that converts vitamin A metabolite retinaldehyde (Rald) to retinoic acid (RA). We hypothesized that this endogenous RA generation mediates sex-specific differences in visceral fat formation. We identified Aldh1A1 as the major enzyme producing RA during adipogenesis in vitro and in mouse visceral fat in vivo. In high-fat-fed Aldh1A1−/− female mice compared to male groups, RA generation in visceral fat was impaired due to decreased Aldh1A2, and Aldh1A3 expression. Accordingly, only female Aldh1A1−/− mice resisted diet-induced visceral obesity and glucose intolerance seen in WT mice. The glucose intolerance was transiently reversed by intraperitoneal RA injections into Aldh1A1−/− females. Global proteomic comparison of WT and Aldh1A1−/− visceral fat revealed that Aldh1A1−/− mice had a subset of proteins changed in a sex-specific manner. Protein changes were mediated by mTORC1/p70S6K inhibition in Aldh1A1−/− females only. In consonance with mTORC1 inhibition, female, but not male Aldh1A1−/− mice had increased thermogenesis. Mechanistic studies demonstrated that RA activated and Rald inhibited mTORC1/p70S6K activation. In the female model of visceral obesity induced by ovariectomy, Aldh1A1 deficiency also suppressed RA generation, inhibited mTORC1/p70S6K, and prevented visceral obesity. Similar mechanisms may be at work in women, who abundantly express Aldh1A1 in visceral adipocytes. Our data suggest a novel signaling role for Rald and RA in the regulation of sex-specific metabolic differences, and propose Aldh1A1 as a candidate target for treatment of visceral obesity in women.
Embargo: A one-year embargo was granted for this item.
Series/Report no.: The Ohio State University. Department of Human Nutrition Honors Theses; 2010
Keywords: Vitamin A regulates female visceral obesity
retinoic acid
mammalian target of rapamycin
estrogen
female obesity
ovariectomy
alcohol dehydrogenase
Raldh-1
Sponsors: University Honors and Scholars Center, The Ohio State University
College of Education and Human Ecology, The Ohio State University
Description: My thesis proposal was awarded the Honors and Scholars Summer Research Scholarship for the summer of 2009.
My thesis proposal was the basis for a Full Undergraduate Research Scholarship in 2009.
URI: http://hdl.handle.net/1811/51796
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