Vitamin D Insufficiency Exacerbates Adipose Tissue Macrophage Infiltration and Decreases AMPK/SIRT1 Activity in Obese Rats

Abstract

Obesity is recognized as a state of chronic low-grade systemic inflammation due to adipose tissue macrophage infiltration and production of proinflammatory adipokines. Decreased vitamin D status is associated with obesity. The specific aim of the present study is to investigate the effects of vitamin D on obesity-induced adipose tissue inflammation. Male Sprague-Dawley rats were randomized and fed a normal diet (NOR, 1000 IU vitamin D/kg diet), a 45% high-fat diet (HF, 1000 IU vitamin D/kg diet), or a 45% high-fat diet containing 25 IU vitamin D/kg diet (HF+LVD) for 12 weeks. The vitamin D-insufficient diet (HF+LVD) led to vitamin D inadequacy as determined by serum 25(OH)D level, 68.56 ± 7.97 nmol/L. The HF+LVD group exacerbated HF-increased adipocyte size, adipogenic gene expression of PPARγ, adipose tissue macrophage recruitment, and proinflammatory cytokine IL-6 and TNFα levels in epididymal white adipose tissue. In addition, vitamin D insufficiency significantly decreased mRNA levels of β-oxidation-related genes such as CPT1α, PGC1α, PPARα, VLCAD, LCAD, MCAD, and UCP1. Moreover, significant decrements of SIRT1 and AMPK activity were noted in obese rats fed with a vitamin D-insufficient diet. The observed deleterious effects of vitamin D insufficiency on adipose tissue expansion, immune cell infiltration and inflammatory status suggest vitamin D plays a beneficial role in adipocyte metabolic metabolism and obesity progression. SIRT1 and AMPK activity may play a role in the mechanism of vitamin D action.

Genetic Factors and Molecular Mechanisms of Vitamin D and Obesity Relationship

“…In addition, as AMPK enhances sirtuin 1 by increasing NAD/NADH ratio and decreases AT macrophage infiltration and inflammation, both have been proposed as key regulators to prevent obesity and obesity-related metabolic dysfunction. A recent study conducted by Chang et al [59] described that vitD deficiency significantly decreased mRNA levels of oxidation-related genes. Moreover, significant decrements of sirtuin 1 and AMPK activity were noted in obese rats fed with a vitD-insufficient diet.…”

“…Consequently, the immune cells play an important role in AT and immune homeostasis. A decreased vitD status is associated with obesity, and recent in vitro studies have described that 1,25(OH) 2 D exerts anti-inflammatory action on adipocytes [48,59]. VitD promotes a lower chemokine and cytokine release by adipocytes and the chemotaxis of monocytes.…”

“…Moreover, significant decrements of sirtuin 1 and AMPK activity were noted in obese rats fed with a vitD-insufficient diet. The observed deleterious effects of vitD deficiency on AT expansion, immune cell infiltration, and inflammatory status suggest that vitD plays a beneficial role in adipocyte metabolic metabolism and obesity progression [59].…”

Micro‐environment and intracellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases

“…1,25(OH) 2 D 3 supplementation has been shown to reduce a unique circulating monocyte cholesterol pool in type 2 diabetes patients, the deficiency of which significantly promoted cholesterol accumulation and polarized macrophages toward the M2 phenotype in LPS‐stimulated THP1‐macrophages by decreasing plasma HDL levels and by decreasing the expression of LXR and ABCA1 . Moreover, decreased VD status reduced FAO‐related genes such as CPT1α, PGC1α, PPARα, and UCP1, and eventually exacerbated ATM infiltration and inflammation in obese rats . These studies suggest that VD is an important link between lipid metabolism and the immune‐inflammatory system.…”

“…Vitamin D (VD), a fat‐soluble vitamin, is well known for its roles in calcium and bone metabolism. Even though it cannot provide energy like sugar and fat, VD plays active roles in metabolism in vivo . Epidemiological studies have shown that VD insufficiency or deficiency is common in obesity‐related metabolic diseases, which has harmful effects on obesity‐induced AT inflammation, including increased AT expansion, immune cell infiltration, and inflammatory status in rodent models .…”