Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex-specific differences in visceral adiposity.

Diabetes. 2013 Jan;62(1):124-36.

Yasmeen R, Reichert B, Deiuliis J, Yang F, Lynch A, Meyers J, Sharlach M, Shin S, Volz KS, Green KB, Lee K, Alder H, Duester G, Zechner R, Rajagopalan S, Ziouzenkova O.

Department of Human Nutrition, The Ohio State University, Columbus, Ohio, USA.



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 non-genomic 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.

PMID: 22933113


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The higher prevalence of obesity in women increases their risk of mortality through the development of life-threatening metabolic diseases [1] . Men and women have different fat distribution patterns. Notably, abdomenal fat accumulation around vital organs (known as visceral fat) is an independent predictor of development of metabolic syndrome and all-cause mortality [2]. Men tend to accumulate more fat in visceral depots, whereas women store more fat in subcutaneous (sc) regions [3]. However, female fat distribution patterning becomes altered once women reach menopause or consume a high fat diet. These changes promote deposition of harmful visceral fat (VF), putting women at greater risk for type 2 diabetes, cardiovascular disease, and even cancer [3]. Thus, understanding the etiology and mechanisms of sex-specific fat deposition is essential to preventing and treating obesity-related ailments.

Obesity is known as a disease of imbalanced energy homeostasis, where energy intake from macronutrients exceeds energy expenditure. The occurrence of obesity due to deregulation of energy storage and expenditure is often underappreciated. Energy is stored in lipid droplets as triglycerides (TG) in differentiated adipocytes. This process in adipocytes is controlled by peroxisome proliferator-activated receptor-gamma (PPARg), a master nuclear regulator of transcription leading to fat formation [4].  White adipose tissue also can expend energy  via generation of heat (thermogenesis) in a rare population of adipocytes (thermocytes) in white adipose tissue [5].  Thermogenesis begins with the release of free fatty acids from TG (lipolysis) and continues with their oxidation in mitochondria. Thermogenesis is mediated by uncoupling protein 1 (UCP1) in thermocytes’  mitochondria. Lipolysis in adipose tissue is governed by the key lipolytic enzyme, adipose triglyceride lipase (ATGL). Free fatty acids released by ATGL can also activate nuclear receptor PPARa, which induces genes regulating fatty acid oxidation and thermogenesis. Induction of thermogenesis has been previously studied in sc fat and found to be an efficient method of burning excess calories and keep weight gain under control. Although some breakthrough has been made regarding our understanding of thermogenesis in sc fat [6], the mechanisms regulating thermogenesis in deleterious VF were unknown and have been identified in our study [7].

Our interest in vitamin A arose from its crucial role in gene transcription and its presence in white adipose tissue [8]. Vitamin A metabolites – retinaldehyde (Rald) and retinoic acid (RA) are known to regulate adipogenesis and triglyceride accumulation. RA is produced solely from Rald by the cytosolic Aldh1 family of enzymes, that comprise of 3 members – Aldh1a1, Aldh1a2, Aldh1a3 [9]. In our previous work, we have shown that Aldh1 enzymes regulate adipogenesis through various transcription factors, including Pparg [9]. We found that differential expression pattern of Aldh1 enzymes play a critical role in different formation of sc and VF in males and females. Female mice deficient in Aldh1a1 (Aldh1a1/) had significantly less VF. In female VF all Aldh1a1, Aldh1a2, and Aldh1a3 were not expressed, suggesting the defective conversion of Rald to RA. In male VF,  Aldh1a2, and Aldh1a3 were expressed and enable RA generation. The differential production of Rald in female and RA in male VF had critical consequences on VF formation. Aldh1a1/ females remained lean and did not develop visceral obesity in contrast to wild type (WT) mice, even on a high-fat diet. Aldh1a1/and WT males both developed VF on this high-fat diet. Proteomic analysis revealed higher protein levels of lipolytic ATGL in the VF of Aldh1a1/females but not males. Moreover, ATGL-expression in Aldh1a1-/- female VF also activated thermogenesis. Elevated thermogenesis in VF increased metabolic rates in these females and prevented weight gain on a high-fat diet. Our ex-vivo studies demonstrated that elevated Rald levels was the underlying cause of sex-specific differences in ATGL protein expression and activity. Thus, our studies revealed a novel non-genomic function of Rald [7].

VF development accompanies menopause in humans and precedes development of metabolic syndrome. To investigate estrogen influence on sex-specific response via Aldh1-dependent pathway, we ovariectomized WT and Aldh1a1/ females. Ovariectomized WT females had increased expression of Aldh1a3 and Rar  target genes (Cyp26A), suggesting increased RA production in the absence of estrogen [7]. Interestingly, the regional differences in fat formation in humans also are associated with Aldh1 enzyme expression. We found increased Aldh1a1 expression in the visceral stromal vascular fraction cells of obese women, suggestive of accelerated preadipocyte differentiation and RA generation in obese compared to lean subjects [7]. Further studies in larger patient cohorts will help us understand whether Aldh1 expression and concentrations of dependent metabolites, RA and Rald, are linked to visceral obesity in humans.

The link between macronutrients, i.e. high-fat diet, and micronutrients, such as RA generation, in sex-specific fat formation was further established using transgenic RARE reporter mice (RAREtg). These mice express β-galactosidase upon RAR activation by endogenous or exogenous RA. We compared beta-galactosidase expression (indicating intrinsic RA production) in these mice upon high fat feeding. RAREtg females had elevated RA generation in VF, while VF of RAREtg males lacked such association. Moreover, RAREtg females had larger proportion of VF compared to males on a high fat diet. Our data suggest a novel mechanism by which high fat diet feeding is linked to RA production, that increases VF formation in sex- and depot-specific manner [7] (Fig. 1).

Diabetes Fig1

Currently, the only available treatments utilizing retinoids are limited to acne/psoriasis treatments by 13-cis RA and acute promyelocytic leukemia by all-trans RA. However, these treatments are associated with serious side effects known as “RA syndrome”, characterized by dyslipidemia and obesity. Therapies down-regulating Aldh1a1 expression could be more efficient. We have developed a novel approach to target Aldh1a1 in an adipose depot-specific fashion. We implanted Aldh1a1-/- fibroblasts containing microcapsules into VF depots and reduced VF formation in obese WT mice fed a high-fat diet [10]. Further studies evaluating the efficiency and safety of this procedure in larger animals would enable translation of Aldh1a1-based therapies to humans.

(Presented by Yasmeen R and Ziouzenkova O.)



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