Targeted Expression of Human Vitamin D Receptor in Adipocytes Decreases Energy Expenditure and Induces Obesity in Mice

Abstract

Our previous studies demonstrated a high fat diet-resistant lean phenotype of vitamin D receptor (VDR)-null mutant mice mainly due to increased energy expenditure, suggesting an involvement of the VDR in energy metabolism. Here, we took a transgenic approach to further define the role of VDR in adipocyte biology. We used the aP2 gene promoter to target the expression of the human (h) VDR in adipocytes in mice. In contrast to the VDR-null mice, the aP2-hVDR Tg mice developed obesity compared with the wild-type counterparts without changes in food intake. The increase in fat mass was mainly due to markedly reduced energy expenditure, which was correlated with decreased locomotive activity and reduced fatty acid ␤-oxidation and lipolysis in the adipose tissue in the transgenic mice. Consistently, the expression of genes involved in the regulation of fatty acid transport, thermogenesis, and lipolysis were suppressed in the transgenic mice. Taken together, these data confirm an important role of the VDR in the regulation of energy metabolism.The maintenance of body weight depends on the balance between energy intake and energy utilization. Obesity results when energy consumed exceeds energy utilized. Energy is acquired through diets and can be stored in adipose tissue or utilized by the body to maintain basic cellular functions and physical activities. Energy can also be used for adaptive thermogenesis in response to a cold environment (1). The adipose tissue is unique in that it represents both arms of energy balance. The white adipose tissue (WAT) 2 has the ability to sense the energy state of the body. When energy availability is high, the WAT stores the excess energy as triglyceride in lipid droplets.When energy is needed, triglyceride is broken down to free fatty acids to release into the circulation. This process, known as lipolysis, is regulated by two enzymes, adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). ATGL initiates the first rate-limiting step of lipolysis by hydrolyzing triglyceride to diacylglyceride (2, 3), which is further broken down to monoglyceride by HSL (4). Monoglyceride lipase cleaves the final ester bond of monoglyceride to release glycerol, and this step is not rate-limiting (5). Lipolysis is activated by catacholamines through the cAMP signaling pathway, leading to protein kinase A activation. Protein kinase A phosphorylates HSL, which promotes HSL translocation to the lipid droplet and access to triglyceride stores (6). HSL and ATGL activity is suppressed by insulin during feeding, as insulin increases the amount of perilipin around the lipid droplets to prevent their access to triglycerides (7).The principal role of the brown adipose tissue (BAT) is to regulate adaptive thermogenesis through the expression of uncoupling proteins (UCPs). UCP1 separates oxidative phosphorylation from ATP production to release energy as heat (8 -10). Studies have shown that increased expression of UCP1 in the BAT or its ectopic expression in the WAT results in increased metabolism...

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

“…In this case, the resistance to diet-induced obesity observed in Vdr −/− mice would be only VDR-dependent and not mediated by its ligand (87) . This would also be the case of human VDR overexpression where a down-regulation of uncoupling protein-1 is associated with weight gain (88) . In the case of Cyp27b1 −/− , the decrease in 1,25(OH) 2 D plasma levels likely results in a decrease of VDR, since VDR is able to induce its own expression (92) , leading to the observed phenotype (86) .…”

“…−/− and human VDR overexpression), phenotype appears tightly linked to uncoupling protein-1 modulation (86)(87)(88) . However, we now know that unliganded VDR can down-regulate uncoupling protein-1 (91) , which means the VDR knockout could trigger an increase in uncoupling protein-1 leading to obesity resistance independently of plasma or adipose tissue levels of 1,25(OH) 2 D or other VD metabolites.…”

“…This phenotype was linked to the co-induction of fatty acid β-oxidation and uncoupling proteins in adipose tissue leading to increased energy expenditure in these mice. Conversely, overexpression of human VDR in mouse adipose tissue induced an obese phenotype characterised by increased weight and fat mass due to decreased energy expenditure, reduced fatty acid β-oxidation and lipolysis (88) . Taken together, these data strongly suggest that VDR or 1,25(OH) 2 D has an impact on overall energy metabolism by acting on adipose tissue biology, but with a number of caveats.…”

Hypoxia and Adipose Tissue Function and Dysfunction in Obesity

“…The lipid secretions include cholesterol and specific prostaglandins, such as PGE 2 and 15-deoxy-PGJ 2 (4,44,45), as well as endocannabinoids, including anandamide (39,58). Adipocytes also store and release the fat-soluble vitamins ␣-tochopherol and vitamin D 3 (6,8,10) and can synthesize active glucocorticoids through the presence of the type 1 form of the enzyme 11␤-hydroxysteroid dehydrogenase, with adipose tissue being an important site in humans of the regeneration of cortisol from cortisone (174 (24,186,196,213).…”

Transgenerational Effects on the Liver and Pancreas Resulting from Maternal Vitamin D Restriction in Mice

“…Vitamin D inhibits the differentiation of adipocytes and may be involved in adipocytes apoptosis (5,6). Specifically, vitamin D may affect the intracellular calcium signaling pathways associated with apoptosis in immature and mature adipocytes.…”