The role of vitamin A in brown fat activation

Obesity is a complex metabolic disorder threatening to affect a significant portion of the world population. Promoting brown fat function has shown promise as a novel approach to increase energy expenditure and combat obesity in preclinical studies. The recent discovery of active brown adipose tissue (BAT) in adult humans has fueled attempts to harness brown fat function therapeutically. To date, no pharmacological strategies exist to harness the thermogenic effects of brown fat in humans. Understanding the molecular mechanisms that lead to chronic BAT activation represents a critical step in the development of novel therapeutic approaches for the treatment of obesity. We and others have recently established that vitamin A metabolism is an important regulator of energy balance through effects on liver, white and brown adipose tissue. Vitamin A is mainly stored in the liver but can be mobilized and shuttled to tissues in demand. Previous studies, including our own, indicate that vitamin A metabolites (retinoids) are potent transcriptional mediators of the key thermogenic factor uncoupling protein-1. However, the specific physiologic role of retinoid metabolism in brown fat activation and adaptive thermogenesis remains undefined. Understanding the biological role of retinoid pathways in the regulation of thermogenic processes, and the translation of such pathways to human physiology could help identify novel therapeutic targets for obesity and associated metabolic complications. Based on preliminary data presented here and previously published work, the central hypothesis of this proposal is that endogenous retinoids mediate thermogenic processes in brown fat, and that the liver acts as a thermogenic reservoir to fuel BAT activation. To test this hypothesis highly integrated specific aims will be pursued. First, we will determine the importance of retinoid metabolism for brown fat thermogenesis using dietary and genetic mouse models of vitamin A deficiency in cold exposure studies (Aim 1). We will then characterize how retinoid metabolism is regulated in response to adrenergic activation. Transcription pathways, retinoid metabolites, and retinoid signaling will be analyzed in vivo and in vitro following adrenergic stimulation (Aim 2). Our preliminary data suggest that hepatic retinoid stores contribute to brown fat activation. Hence, we will explore the role of the liver for adaptive thermogenesis by studying how hepatic retinoids can be mobilized in response to cold and adrenergic signaling (Aim 3). Collectively, the work proposed here will investigate a novel regulatory pathway in BAT activation and provide a platform for exploring novel therapeutic approaches in the treatment of obesity and metabolic dysregulation.

Vitamin A boosts fat burning in cold conditionsA recent study conducted by a research team led by Florian Kiefer from MedUni Vienna`s Division of Endocrinology and Metabolism shows that cold ambient temperatures increase vitamin A levels in humans and mice. This helps convert bad white adipose tissue into good brown adipose tissue which stimulates fat burning and heat generation. This "fat transformation" is usually accompanied by enhanced energy consumption and is therefore considered a promising approach for the development of novel obesity therapeutics. The study has now been published in the leading journal Molecular Metabolism. In humans and mammals, at least two types of fatty depots can be discerned, white and brown adipose tissue. During obesity development, excess calories are mainly stored in white fat. In contrast, brown fat burns energy and thereby generates heat. More than 90% of the body fat depots in humans are white which are typically located at the abdomen, bottom, and upper thighs. Converting white into brown fat could be a new therapeutic option to combat weight gain and obesity. A research group led by Florian Kiefer from the Division of Endocrinology and Metabolism at MedUni Vienna demonstrated now that moderate application of cold increases the levels of vitamin A and its blood transporter, retinol-binding protein, in humans and mice. Most of the vitamin A reserves are stored in the liver and cold exposure seems to stimulate the redistribution of vitamin A towards the adipose tissue. The cold-induced increase in vitamin A led to a conversion of white fat into brown fat (browning), with a higher rate of fat burning. When Kiefer and his team blocked the vitamin A transporter "retinol-binding protein" in mice by genetic manipulation, both the cold-mediated rise in vitamin A and the "browning" of the white fat were blunted: "As a consequence, fat oxidation and heat production were perturbed so that the mice were no longer able to protect themselves against the cold," explains Kiefer. In contrast, the addition of vitamin A to human white fat cells led to the expression of brown fat cell characteristics, with increased metabolic activity and energy consumption."Our results show that vitamin A plays an important role in the function of adipose tissue and affects global energy metabolism. However, this is not an argument for consuming large amounts of vitamin A supplements if not prescribed, because it is critical that vitamin A is transported to the right cells at the right time," explains the MedUni Vienna researcher. "We have discovered a new mechanism by which vitamin A regulates lipid combustion and heat generation in cold conditions. This could help us to develop new therapeutic interventions that exploit this specific mechanism."