Intact vitamin A transport is critical for cold-mediated adipose tissue browning and thermogenesis

Abstract

Objective Transformation of white into brown fat (“browning”) reduces obesity in many preclinical models and holds great promise as a therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue; however, the physiologic importance of systemic retinoid transport for adipose tissue browning and adaptive thermogenesis is unknown. Methods We performed cold exposure studies in mice and humans and used a genetic model of defective vitamin A transport, the retinol binding protein deficient (Rbp −/- ) mouse, to study the effects of cooling on systemic vitamin A and the relevance of intact retinoid transport on cold-induced adipose tissue browning. Results We show that cold stimulation in mice and humans leads to an increase in circulating retinol and its plasma transporter, Rbp. In Rbp −/- mice, thermogenic programming of adipocytes and oxidative mitochondrial function are dramatically impaired in subcutaneous white fat, which renders Rbp −/- mice more cold-sensitive. In contrast, retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In humans, cold-mediated retinol increase is associated with a shift in oxidative substrate metabolism suggestive of higher lipid utilisation. Conclusions Systemic vitamin A levels are regulated by cold exposure in mice and humans, and intact retinoid transport is essential for cold-induced adipose tissue browning and adaptive thermogenesis.

Biological Functions of RBP4 and Its Relevance for Human Diseases

“…Exposing mice or humans to low temperatures increases plasma concentrations of RBP4 and retinol ( Fenzl et al, 2020 ). In mice, this coincides with an elevation of RBP4 mRNA expression in liver ( Fenzl et al, 2020 ), which may indicate increased retinol mobilization from liver into the blood stream for supporting the adaptation to cold. Indeed, mice lacking RBP4 failed to induce thermogenic reprogramming of their subcutaneous adipose tissue, rendering these mice more sensitive to cold and dropping of their body temperature.…”

“…Indeed, mice lacking RBP4 failed to induce thermogenic reprogramming of their subcutaneous adipose tissue, rendering these mice more sensitive to cold and dropping of their body temperature. Retinol induced thermogenic gene expression also in human white adipocytes and increased mitochondrial respiration ( Fenzl et al, 2020 ). Thus, elevated retinol mobilization by RBP4 from liver upon the exposure to cold may be required for an adequate thermogenic adaptation of specific white adipose tissues depots in order to maintain body core temperature, which so far has not been formally tested.…”

“…Thus, elevated retinol mobilization by RBP4 from liver upon the exposure to cold may be required for an adequate thermogenic adaptation of specific white adipose tissues depots in order to maintain body core temperature, which so far has not been formally tested. Moreover, loss of RBP4 in mice was associated with reduced phosphorylation of hormone sensitive lipase during the exposure to cold ( Fenzl et al, 2020 ), a lipolytic enzyme that is activated by phosphorylation and essential for adequate fatty acid release from white adipose tissue ( Stralfors and Belfrage, 1983 ). Providing fatty acids is required for uncoupling protein-induced thermogenesis ( Schreiber et al, 2017 ).…”

Mechanistic aspects of carotenoid health benefits – where are we now?

“…Animal (207) and human (208)(209)(210)(211) studies have revealed a differential expression of genes for carotenoid/retinoid-metabolising enzymes in visceral and subcutaneous adipose tissues, which display important differences regarding developmental origin, metabolism, endocrinology, capacity for adipogenesis and the health risk they entail (212,213) . Genetic ablation of different carotenoid/ retinoid-metabolising enzymes and transport proteins results in alterations of adiposity and defects in brown adipose tissue (BAT) thermogenesis in mice (200,214,215) Furthermore, adipocyte functions such as the thermogenic capacity of BAT in rodents are dependent on the animal's vitamin A status (212,214,216) .…”

Adipose-Derived Lipid-Binding Proteins: The Good, the Bad and the Metabolic Diseases

“…Even if the RBP4 signaling is not entirely deciphered, many publications tend to demonstrate the negative effect of RBP4 on metabolism and how it can be a promising therapeutic target. In addition, a recent study from Fenzl et al showed that RBP4 is critical in humans and mice for adipose adaptative thermogenesis during a cold exposure [ 33 ]. This discovery highlights new perspectives on RBP4 role in adipose tissue and metabolism, maybe not as detrimental as it first appeared.…”