OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21

Abstract

Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response, by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.

Batokines: Mediators of Inter-Tissue Communication (a Mini-Review)

“…Other studies have showed that non-thermogenic modalities of increasing BAT activity and mass, through methods like BAT transplantation [12], also lead to an increase serum FGF21. These findings along with other recent studies could suggest that the secretion of BATderived FGF21 and its subsequent metabolic effects may not be specifically linked to BAT thermogenic activity [36].…”

Combining Metabolomics and Experimental Evolution Reveals Key Mechanisms Underlying Longevity Differences in Laboratory Evolved Drosophila melanogaster Populations

“…Branched chain amino acids (BCAA), including leucine, isoleucine, and valine, play a crucial role in the activation of the TOR pathway [71]. Mitochondrial stress can be regulated by Tor through activation of ATF4 to induce the integrated stress response and activation of GCN2 to increase amino acid availability [72][73][74][75][76][77][78][79][80], which we believe to be a protective response. We hypothesize that the lower BCAA levels in the A population (Figure 2D(i)) indicate that they are not able to effectively activate this pathway.…”

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases

“…Elevated levels of FGF21 (both circulation and mRNA) have been observed in cases of several metabolic disorders (NAFLD, obesity, T2DM), which suggests protective activities against those diseases [208]. In addition, FGF21 could be secreted from the brown adipose tissue and participate in thermoregulation in an ATF4-dependent way [209]. Several FGF21 analogues have been clinically tested as promising NAFLD treatments.…”