Retinoic Acid: Sexually Dimorphic, Anti-Insulin and Concentration-Dependent Effects on Energy

Abstract

This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other understudied topics essential for understanding RA activities—especially interactions with energy-balance-regulating hormones, including insulin and glucagon, and sex hormones. This report will introduce RA homeostasis and hormesis to provide context. Essential context will also encompass RA effects on adiposity, muscle function and pancreatic islet development and maintenance. These comments provide background for explaining interactions among insulin, glucagon and cortisol with RA homeostasis and function. One aim would clarify the often apparent RA contradictions related to pancreagenesis vs. pancreas hormone functions. The discussion also will explore the adverse effects of RA on estrogen action, in contrast to the enhancing effects of estrogen on RA action, the adverse effects of androgens on RA receptors, and the RA induction of androgen biosynthesis.

The conversion of β-carotene to vitamin A in adipocytes drives the anti-obesogenic effects of β-carotene in mice

“…These findings align with those from Dr. Joseph L. Napoli's group, which showed sexual dimorphism in several experimental models of obesity. His studies on the role of retinol dehydrogenase 1 and 10, which catalyze the oxidation of retinol to retinal, highlight the importance of studying both genders in metabolic studies in general, and vitamin A metabolism in particular [ 52 ].…”

The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription

“…Because RA exerts concentration-dependent actions (hormesis), chow diets with copious vitamin A have altered phenotypes of at least three retinoid-related gene knockouts, Rdh1 , Rbp4 , and Crbp2 ( Quadro et al., 1999 ; E et al., 2002 ; Zhang et al., 2007 ). Diets copious in vitamin A also impair glucoregulatory mechanisms ( Kane et al., 2011 ; Napoli, 2022 ), which were not evaluated in the Cyp26a1 knockout.…”

Retinoid homeostasis in major depressive disorder

“…Gender differences and sex-specific retinoid dynamics in adult humans are scarcely discussed in the literature. Some support for gender differences in retinoid homeostasis comes from preclinical studies showing sex-specific expression patterns of retinoid receptors, heterogeneous retinol distribution across the brain areas of males and females, and strong effects of sex hormones on RA activities [ 58 – 60 ].…”