Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet-induced mouse model of obesity

Abstract

Background: Retinoic acid (RA) controls diverse physiological functions including weight regulation and energy metabolism. It has been reported that mice lacking ALDH1A1, one of the aldehyde dehydrogenases (ALDH) that synthesize RA, are healthy and resistant to weight gain, raising the possibility that inhibiting this enzyme might treat obesity. We previously demonstrated that treatment with a pan-ALDH1A enzyme inhibitor, WIN18446, suppressed weight gain in mice fed a high fat diet (HFD), but caused increased hepatic lipidosis and reversible male infertility. Methods: A series of piperazine compounds that inhibited ALDH1A1 were identified and their inhibitory activity was characterized in vitro using purified recombinant enzymes and cell-based assay systems. One potent compound, FSI-TN42 (N42) was examined for its oral bioavailability and pharmacodynamic effects. In addition, its effect on weight gain was investigated by daily oral administration to C57BL/6 male mice receiving a HFD, and compared with mice receiving WIN18446 or vehicle alone (n=6/group, 200 mg compound/kg body weight) for 5 weeks. Body weights were measured weekly, and a glucose tolerance test was performed after 4 weeks of treatment. Tissues were collected to determine changes in adipose weight, hepatic lipidosis, retinoid metabolism, and expression of genes associated with RA and lipid metabolism. Results: N42 irreversibly binds and inhibits ALDH1A1 in vitro with a low nM IC 50 and 800-fold specificity for ALDH1A1 compared to ALDH1A2. Daily oral administration of N42 significantly suppressed weight gain (P<0.05) and reduced visceral adiposity (p<0.05) in mice fed a HFD without the hepatic lipidosis observed with WIN18446 treatment. Conclusions: We developed a potent and specific inhibitor of ALDH1A1 that suppressed weight gain in mice fed a HFD. These findings demonstrate that inhibition of ALDH1A1 is a feasible target for drug development to treat and/or prevent obesity.

The Combined Partial Knockdown of CBS and MPST Genes Induces Inflammation, Impairs Adipocyte Function-Related Gene Expression and Disrupts Protein Persulfidation in Human Adipocytes

“…ADH1B modulates intracellular lipid accumulation, without impacting adipogenesis [ 41 ], and preserved insulin-stimulated glucose uptake in adipocytes [ 42 ]. Inhibition of ALDH1A1 reduced visceral fat [ 43 ], negatively impacting adipogenesis in visceral adipose tissue [ 44 ]. LGALS1 (galectin 1) is an adipocyte secreted factor [ 45 ] that enhances the transcriptional activity of PPARG, increasing adipogenesis and accumulation of lipids in adipocytes [ 46 ].…”

ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism

“…In 2015, Kesharwani et al reported a new approach for overcoming drug resistance to breast chemotherapy via the targeting of synthetic curcumin analogs against ALDH1A (37) potent and selective ALDH1A1 inhibitors (8). It has been proven that N42 could also selectively bind to and inhibit ALDH1A1 (9). Several ALDH1A1-based cancer prevention and treatment measures have been developed.…”

“…Recently, benzimidazole derivatives have been found to act as potent and selective ALDH1A1 inhibitors ( 8 ). It has been proven that N42 could also selectively bind to and inhibit ALDH1A1 ( 9 ).…”

“…In the past decade, researchers have found that ALDH1A1 had vital physiological and pathophysiological functions in many systems, such as the central nervous system, as well as inflammatory and metabolic disorders (5)(6)(7). ALDH1A1 overexpression has been found to play an important role in obesity, diabetes, and other diseases (8)(9)(10)(11)(12)(13). Because the retinoic acid (RA) signaling pathway is involved in the regulation of gene expression in cancer stem cells (CSCs), researchers have focused on the role of ALDH1A1 in cancers worldwide (14)(15)(16).…”

Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

“… 13 Moreover, ALDH1A1‐specific inhibitors have been shown to protect mice on a high‐fat diet from progressive body weight gain and adiposity and accordingly have been proposed as a novel treatment strategy for obesity. 14 , 15 These collective findings underscore the importance of delineating at RA‐synthesizing pathways in metabolic tissues specifically in humans, both to better understand apparent discord between preclinical and clinical data and to inform the design of targeted therapeutics for obesity.…”