The crucial role of muscle glucocorticoid signaling in accelerating obesity and glucose intolerance via hyperinsulinemia

Abstract

Metabolic crosstalk from skeletal muscle to multiple organs is important for maintaining homeostasis, and its dysregulation can lead to various diseases. Chronic glucocorticoid administration often induces muscle atrophy and metabolic disorders such as diabetes and central obesity; however, the detailed underlying mechanism remains unclear. We previously reported that the deletion of glucocorticoid receptor (GR) in skeletal muscle increases muscle mass and reduces fat mass through muscle-liver-fat communication under physiological conditions. In this study, we show that muscle GR signaling plays a crucial role in accelerating obesity through the induction of hyperinsulinemia. Fat accumulation in liver and adipose tissue, muscle atrophy, hyperglycemia, and hyperinsulinemia induced by chronic corticosterone (CORT) treatment improved in musclespecific GR knockout (GRmKO) mice. Such CORT-induced fat accumulation was alleviated by suppressing insulin production (streptozotocin injection), indicating that hyperinsulinemia enhanced by muscle GR signaling promotes obesity. Strikingly, glucose intolerance and obesity in ob/ob mice without CORT treatment were also improved in GRmKO mice, indicating that muscle GR signaling contributes to obesity-related metabolic changes, regardless of systemic glucocorticoid levels. Thus, this study provides new insight for the treatment of obesity and diabetes by targeting muscle GR signaling.

Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production

“…It is well known that insulin plays a crucial role in both adipogenesis and lipogenesis, and the deletion of the constitutive insulin receptor (IR) in adipocytes causes lipodystrophy [23]. Intriguingly, recent studies newly evidenced that GCs excess causes hyperinsulinemia, which is a primary factor inducing central obesity [24]. In the present study, OVX increased circulating GCs and caused hyperinsulinemia, while FGF21 LKO completely reversed OVX-induced high GCs and caused hypoinsulinemia in mice.…”

Pharmacological inhibition of lipolysis prevents adverse metabolic outcomes during glucocorticoid administration

“…In light of the findings by Yamazaki et al. [ 49 ], we speculate that these protective effects are due to the fact that Atglistatin mitigated the rise in circulating insulin (and hyperglycemia) during Cort exposure.…”

“…Recently, Yamazaki et al. [ 49 ] provided key insight into this conundrum as they confirm that gains in adiposity induced by glucocorticoids require the development of hyperinsulinemia. This also provides insight into observations from the present study.…”