The Role of Vitamin D in Obesity and Diabetes: Ca2+ Signaling, Insulin Secretion, Adipocyte Apoptosis, and Bone Mineralization

Abstract

Vitamin D has been linked to obesity and type 2 diabetes (T2D) in observational studies, and low vitamin D status is considered a risk factor for these interrelated diseases. However, mechanistic understanding of the role of vitamin D hormone, 1,25(OH)2‐vitamin D3, in obesity and T2D is lacking. We showed that 1,25(OH)2D3‐dependent cellular Ca2+ signals regulate apoptotic death of adipocytes and insulin secretion from pancreatic β‐cells (Sergeev, 2014, 2013, 2009, 2005, 2004). The anti‐obesity effects of 1,25(OH)2D3 in mature adipocytes are determined by its activity to generate, via multiple Ca2+ signaling pathways, a sustained increase in intracellular Ca2+ followed by activation of Ca2+‐dependent initiators and effectors of apoptosis. In pancreatic β‐cells, 1,25(OH)2D3 induces synchronous Ca2+ oscillations, which quantitatively, temporally and spatially pattern oscillatory insulin release from these cells. In recent studies, we examined the effects of increased intake of vitamin D and Ca in a mouse model of high fat diet‐induced obesity (DIO) on development of adiposity and diabetes. DIO mice were characterized by obese phenotype, elevated blood glucose and impaired glucose tolerance, increased insulin and decreased adiponectin concentrations in blood, decreased level of apoptosis in adipose tissue, and decreased Ca and P content in bone. Mice fed high fat diet (DIO) with high vitamin D3 and increased Ca content demonstrated a decreased weight of white adipose tissue depots and improved blood markers related to adiposity, T2D, and vitamin D status. Fasting plasma glucose and insulin concentrations in these mice were significantly decreased, approaching levels found in normal‐weight, non‐obese control, whereas adiponectin concentration demonstrated an increasing trend. DIO was accompanied by low vitamin D status (a decreased level of 25(OH)D) and a decreased plasma concentration of 1,25(OH)2D3. High vitamin D3 intake induced a significant increase in plasma concentrations of 25(OH)D and 1,25(OH)2D3, indicating high vitamin D nutritional status and normal vitamin D hormonal status. High vitamin D3 and Ca intakes were associated with induction of apoptosis (oligonucleosomal fragmentation and ssDNA breaks) and activation of Ca2+‐dependent apoptotic proteases (calpain and caspase‐12) in adipose tissue of DIO mice. High vitamin D3 and Ca intakes were effective in normalization (an increase) of mineral (Ca and P) content in the growing bone of DIO mice via regulatory effects mediated by 1,25(OH)2D3 ‐ PTH axis. The major results obtained demonstrate that increased vitamin D and Ca intake is highly effective in decreasing blood glucose and insulin in DIO and that the hormonal mechanism of this effect can involve 1,25(OH)2D3. Increasing vitamin D and Ca intakes in obesity also activates Ca2+‐mediated apoptotic pathway in adipocytes resulting in a decreased mass of fat tissue and improved markers of adiposity. Moreover, high vitamin D and Ca intakes improve bone status in obesity by increasing bone mineralization via PTH/1,25(OH)2D3‐mediated regulation. The findings obtained strongly imply that increasing vitamin D and Ca intakes may contribute to prevention of obesity, T2D, and bone disorders associated with these diseases.Support or Funding InformationSupported by USDA 2009‐35200‐05008 and SD00H533.