Autocrine Function of Aldehyde Dehydrogenase 1 as a Determinant of Diet- and Sex-Specific Differences in Visceral Adiposity

Abstract

Mechanisms for sex- and depot-specific fat formation are unclear. We investigated the role of retinoic acid (RA) production by aldehyde dehydrogenase 1 (Aldh1a1, -a2, and -a3), the major RA-producing enzymes, on sex-specific fat depot formation. Female Aldh1a1−/− mice, but not males, were resistant to high-fat (HF) diet–induced visceral adipose formation, whereas subcutaneous fat was reduced similarly in both groups. Sexual dimorphism in visceral fat (VF) was attributable to elevated adipose triglyceride lipase (Atgl) protein expression localized in clusters of multilocular uncoupling protein 1 (Ucp1)-positive cells in female Aldh1a1−/− mice compared with males. Estrogen decreased Aldh1a3 expression, limiting conversion of retinaldehyde (Rald) to RA. Rald effectively induced Atgl levels via nongenomic mechanisms, demonstrating indirect regulation by estrogen. Experiments in transgenic mice expressing an RA receptor response element (RARE-lacZ) revealed HF diet–induced RARE activation in VF of females but not males. In humans, stromal cells isolated from VF of obese subjects also expressed higher levels of Aldh1 enzymes compared with lean subjects. Our data suggest that an HF diet mediates VF formation through a sex-specific autocrine Aldh1 switch, in which Rald-mediated lipolysis in Ucp1-positive visceral adipocytes is replaced by RA-mediated lipid accumulation. Our data suggest that Aldh1 is a potential target for sex-specific antiobesity therapy.

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

“…Sexual dimorphisms have been observed in several mouse models of obesity (55) and diabetes (56,57). Vitamin A metabolism may be important in these sexual dimorphisms, since female mice, but not male mice, with a block in vitamin A metabolism are resistant to the high-fat-diet-induced formation of visceral fat (58).…”

Genetic Basis for Sex Differences in Obesity and Lipid Metabolism

“…Another potential effector of sex hormone effects on adipose tissue depot expansion may be the enzyme aldehyde dehydrogenase 1 (Aldh1a1) (119). Deletion of Aldh1a1 abrogated diet-induced expansion of subcutaneous fat in male and female mice compared to wild-type animals.…”

Enzymatic intracrine regulation of white adipose tissue

“…In WAT, thermogenesis can be induced by either sympathetic nerve stimulation, prolonged cold exposure [21], or consumption of high-fat and spicy diets [22]. Induction of thermogenesis in WAT can change energy homeostasis and effectively decrease obesity and insulin resistance [9, 23, 24]. Notably, the increased proportion of thermogenic to lipogenic adipocytes in abdominal fat can decrease lipid accumulation in this deleterious depot [23].…”

“…Rald is known primarily for its role in the eye (reviewed in [138]), but in WAT, Rald regulates adipogenesis through inhibition of RXR and PPARγ [139]. Rald also mediates non-genomic effects leading to rapid translation of ATGL, activation of lipolysis, and subsequent activation of thermogenesis in visceral WAT [9]. Direct molecular targets of Rald that mediate transcription and signaling have not been reported.…”

“…The understanding of the mechanisms responsible for fat depot formation appears to be a critical issue, because abdominal obesity greatly increases risks for metabolic syndrome, type 2 diabetes, coronary heart disease, stroke, and certain cancers [3, 4]. The propensity to develop abdominal obesity and other metabolic risk factors appears to depend on heritable genetic factors [5, 6], endocrine status [7, 8], and specific ‘zero calorie’ micronutrients [9]. The abdominal and other fat depots have autonomous regulatory circuits that locally produce hormones from inactive precursors or nutrients for intra-/auto-/paracrine signaling (referred to as ‘intracrine’ circuits in this review).…”