Chronic hyperinsulinemia reduces insulin sensitivity and metabolic functions of brown adipocyte

Abstract

The growing pandemics of diabetes have become a real threat to world economy. Hyperinsulinemia and insulin resistance are closely associated with the pathophysiology of type 2 diabetes. In pretext of brown adipocytes being considered as the therapeutic strategy for the treatment of obesity and insulin resistance, we have tried to understand the effect of hyperinsulinemia on brown adipocyte function. We here with for the first time report that hyperinsulinemia-induced insulin resistance in brown adipocyte is also accompanied with reduced insulin sensitivity and brown adipocyte characteristics. CI treatment decreased expression of brown adipocyte-specific markers (such as PRDM16, PGC1α, and UCP1) and mitochondrial content as well as activity. CI-treated brown adipocytes showed drastic decrease in oxygen consumption rate (OCR) and spare respiratory capacity. Morphological study indicates increased accumulation of lipid droplets in CI-treated brown adipocytes. We have further validated these findings in vivo in C57BL/6 mice implanted with mini-osmotic insulin pump for 8 weeks. CI treatment in mice leads to increased body weight gain, fat mass and impaired glucose intolerance with reduced energy expenditure and insulin sensitivity. CI-treated mice showed decreased BAT characteristics and function. We also observed increased inflammation and ER stress markers in BAT of CI-treated animals. The above results conclude that hyperinsulinemia has deleterious effect on brown adipocyte function, making it susceptible to insulin resistance. Thus, the above findings have greater implication in designing approaches for the treatment of insulin resistance and diabetes via recruitment of brown adipocytes.

A causal role for hyperinsulinemia in obesity

“…Collectively, these experiments also fit well with clinical and pre-clinical studies demonstrating that therapy with long-acting insulin analogues leads to weight gain, and with small trials showing weight loss with drugs that reduce insulin secretion (Alemzadeh et al 1998, Lustig et al 2005, ORIGIN Trial Investigators et al 2012, Skovso et al 2015. For example, a recent investigation reported that chronic insulin infusion via mini-osmotic pump leads to WAT expansion in mice (Rajan et al 2016). Clearly, more work needs to be done, but the idea that insulin plays an important role in lipid homeostasis in vivo appears to be broadly supported.…”

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

“…Since chronic hyperinsulinemia can lead to the development of insulin resistance (Gray et al, 2010; Rajan et al, 2016), our data suggest that early hyperinsulinemia in SIRT4KO mice may be the primary defect driving accelerated age-induced insulin resistance. As a whole, our data support the notion that SIRT4 controls leucine metabolism and insulin secretion in islets and that loss of SIRT4 leads to dysregulated insulin secretion and accelerated age-induced glucose intolerance and insulin resistance.…”

“…Interestingly, the earliest defect we observed in SIRT4KO mice was basal hyperinsulinemia. While this phenotype was mild, previous studies have shown that chronic hyperinsulinemia can lead to insulin resistance (Coleman and Hummel, 1974; Gray et al, 2010; Lee, 1981; Rajan et al, 2016). Indeed, as SIRT4KO mice aged, the hyperinsulinemia became progressively worse, which was consistent with the development of glucose intolerance, insulin resistance, and fasting hyperglycemia.…”

Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue

“…Brown adipose tissue plays important roles in adaptive thermogenesis (nonshivering thermogenesis) for the maintenance of basic body temperature and heat balance energy against cold [21, 22]. Stress-related alterations in endoplasmic reticulum, such as the unfolded protein response (UPR), are associated with obesity [23].…”