Abstract
Endoplasmic reticulum (ER) stress, inflammation, and lipolysis occur simultaneously in adipose dysfunction and contribute to insulin resistance. This study was designed to investigate whether ginsenoside Rg5 could ameliorate adipose dysfunction and prevent muscle insulin resistance. Short-term high-fat diet (HFD) feeding induced hypoxia with ER stress in adipose tissue, leading to succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activity. Rg5 treatment reduced cellular energy charge, suppressed ER stress and then prevented succinate accumulation in adipose tissue. Succinate promoted IL-1β production through NLRP3 inflammasome activation and then increased cAMP accumulation by impairing PDE3B expression, leading to increased lipolysis. Ginsenoside Rg5 treatment suppressed NLRP3 inflammasome activation, preserved PDE3B expression and then reduced cAMP accumulation, contributing to inhibition of lipolysis. Adipose lipolysis increased FFAs trafficking from adipose tissue to muscle. Rg5 reduced diacylglycerol (DAG) and ceramides accumulation, inhibited protein kinase Cθ translocation, and prevented insulin resistance in muscle. In conclusion, succinate accumulation in hypoxic adipose tissue acts as a metabolic signaling to link ER stress, inflammation and cAMP/PKA activation, contributing to lipolysis and insulin resistance. These findings establish a previously unrecognized role of ginsenosides in the regulation of lipid and glucose homeostasis and suggest that adipose succinate-associated NLRP3 inflammasome activation might be targeted therapeutically to prevent lipolysis and insulin resistance.
Highlights
Adipose tissue functions as a site for fat storage, whereas disordered fat storage and mobilization are tightly associated with insulin resistance and diabetes
To know the possible mechanism through which Rg5 prevented adipose hypoxia, we investigated the effects of Rg5 on cellular energy charge in adipocytes
We showed that short-term high-fat diet (HFD) feeding induced hypoxia in adipose tissue of mice
Summary
Adipose tissue functions as a site for fat storage, whereas disordered fat storage and mobilization are tightly associated with insulin resistance and diabetes. It is generally accepted that adipose hypoxia is a result of increased fat mass size (Skurk et al, 2007; Trayhurn, 2013; Muniyappa and Sowers, 2014). Rg5 Prevents Lipolysis-Induced Insulin Resistance saturated fatty acids induce adipose hypoxia through increasing oxygen consumption in adipocytes without alternation in the fat mass size (Lee et al, 2014). This finding sheds new insight into the impact of lipid challenge in adipose dysfunction. Hypoxia induces endoplasmic reticulum (ER) stress in adipose tissue. ER stress, and lipolysis simultaneously occur in adipose dysfunction (Kawasaki et al, 2012; Trayhurn, 2013), the mechanisms and unifying framework for these events are not yet fully understood
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