A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling

Abstract

Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by the hypothalamus-pituitary-adrenal signalling axis via a glucocorticoid-driven transcriptional programme. Here we unravel the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. Metabolically, GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this skeletal muscle-liver-fat signalling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity.

Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy

“…Interestingly, GR (NR3C1) occupancy demonstrated a dose-dependent difference in occupancy of the Klf15 promoter, suggesting that the level of GR occupancy elicits differential effects. Muscle-specific deletion of the GR results in larger muscle mass and a reduction in adipose tissue, demonstrating crosstalk between these tissues (56). Furthermore, mTOR can counterbalance GR effects in muscle and thus may also represent a means of subverting aspects of the atrophy pathway triggered by daily steroid dosing (55).…”

A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution

“…Evidence is emerging, however, that hepatic FGF21 can also be regulated by NEAA supply. For instance, mice with relative hepatic asparagine/glutamine (48,49) or alanine (50) insufficiency also have higher hepatic and circulating FGF21 levels. Consistent with these observations, our data provide evidence that hepatocyte FGF21 induction following DPD occurs in response to an insufficiency of NEAAs, specifically Ala, Gln/Glu, and Asn/Asp.…”

The Effects of Resistance and Endurance Training on the Liver Tissue FNDC5 mRNA Gene Expression in Male Rats

“…Organs involved in fuel storage, such as the liver, the skeletal muscle and adipose tissues all communicate with each other and determine fuel selection and delivery under the strict control of neuroendocrine system (1). The liver stores energy as glycogen and stores digested triglycerides in the form of fatty acids (2).…”