Inhibition of the CD36 receptor reduces visceral fat accumulation and improves insulin resistance in obese mice carrying the BDNF-Val66Met variant

Abstract

Running title: CD36 inhibition improves metabolic dysfunction in obese miceKey words: CD36, diabetes, insulin resistance, obese, salvianolic acid B AbstractObesity-induced metabolic dysfunctions increase risk of vascular diseases including type II diabetes and stroke. While managing obesity is an interest to address the worldwide health problem, how genetic variability affects human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A single nucleotide polymorphism (SNP) in the brain derived neurotropic factor (BDNF) gene that results in the substitution of a valine to a methionine at codon 66 (val66met) occurs with a high frequency in humans. This study addressed the effect of genetic variability in developing obesity and the efficacy of the inhibition of CD36, a multifunctional receptor implicated in obesity and insulin resistance, in wild-type mice and mice with the bdnf val66met variant. CD36 inhibition by salvionolic acid B (SAB) in diet-induced obese wild-type mice reduced visceral fat accumulation and improved insulin resistance. The benefit of SAB was aborted in CD36 knockout mice, showing the specificity of SAB. In addition, mice with the val66met variant in both alleles (BDNF M/M ) fed high-fat diet exhibited extreme obesity with increased CD36 gene and protein levels in macrophages. Chronic SAB treatment in BDNF M/M mice significantly decreased visceral fat accumulation and improved insulin resistance. Notably, the effect of SAB was greater in the extreme obese BDNF M/M mice compared to the wild-type mice. The study demonstrated a link between bdnf val66met and elevated CD36 expression, and suggested that CD36 inhibition may be a novel strategy to improve metabolic dysfunctions and to normalize risk factors for vascular diseases in the obese population.

Lymphocytes upregulate CD36 in adipose tissue and liver

“…CD36 expression and signalling are involved in inflammation and disease pathologies. We observed that CD36 expression in adipose T cells was increased in mice fed a western diet (Figure 5(a)), which may have relevance to the findings that associate higher expression of CD36 in adipocytes and adipose tissue macrophages to obesity and inflammation [10][11][12][13][14]. Recent studies have also shown that CD36 expression and fatty acid uptake in cancer cells can be increased by adipocytes and high-fat diet, resulting in significantly enhanced survival and metastases [15][16][17].…”

“…Expression of CD36 and fatty acid uptake are linked to a number of diseases and pathologies. For example, increased expression of CD36 in adipocytes and adipose tissue macrophages is associated with obesity and inflammation [10][11][12][13][14]. CD36 can be upregulated in cancer cells by adipocytes and high-fat diet to increase fatty acid uptake and promote tumour growth and metastases [15][16][17].…”

Receptor CD36 links a risk-associated allele to obesity and metabolic disorders

“…Yang et al (6) used a unique mouse model containing the human BDNF Val66Met variant and found that, consistent with observations in humans, BDNF M/M mice fed a normal diet had significantly increased body weight relative to BDNF V/V controls by 6 weeks of age. When subsequently fed a high-fat diet for 8 weeks, the BDNF M/M mice became extremely obese with elevated fasting glucose levels and impaired glucose tolerance, implying the development of insulin resistance.…”

“…CD36 is thought to mediate cross-talk between adipocytes and macrophages in obese mice by facilitating cytokine secretion from macrophages (8). To identify the role of CD36 in the development of obesity in BDNF M/M mice, Yang et al (6) used salvianolic acid B (SAB), a specific CD36 antagonist, in experiments both in vitro and in vivo (9). Although chronic administration of SAB into diet-induced obese (DIO) WT mice had no effect on total body weight during the experimental period (8 weeks), it significantly reduced the accumulation of visceral fat and improved glucose tolerance relative to DIO mice receiving the vehicle.…”

Vitamin E: Regulatory Role on Signal Transduction

“…CD36 can influence the response to insulin in a tissue specific manner, as in muscle of mice CD36 deficiency increases insulin sensitivity but, in the liver, it induces insulin resistance, most likely as result of increased cellular fatty acids uptake rather than the presence of fatty acids in plasma (185). In obese mice with elevated CD36 expression due to a polymorphism in the brain-derived neurotrophic factor, inhibition of CD36 by salvianolic acid B improved visceral fat accumulation and insulin resistance (186). These results suggest that by reducing CD36 surface expression and intracellular lipid accumulation, and by modulating the CD36/PI3K/Aktsignaling pathway via hTAP1/SEC14L2 mediated lipid exchange, αT and more so αTP may prevent the development of insulin resistance and excess intracellular lipid accumulation (41,118).…”