# β3-adrenergic receptor agonist causes acute thermogenic metabolic crisis in ACSS1-K635Q knock-in mice

## TL;DR

This study shows that a genetic mutation in ACSS1 causes a severe metabolic crisis in mice when exposed to a β3-adrenergic receptor agonist.

## Contribution

The study reveals a novel role for non-acetylated ACSS1 in thermoregulation and fatty acid metabolism.

## Key findings

- Acss1K635Q/K635Q mice showed hypothermia and metabolic failure after CL-316243 injection.
- Mitochondria from mutant mice had impaired respiration and unresponsive lipid metabolism.
- Beige adipocytes from mutants displayed reduced fatty acid oxidation and altered UCP1 regulation.

## Abstract

Mitochondrial Acyl-Coenzyme Synthetase Short Chain Family Member-1 (ACSS1) converts free acetate into acetyl-coenzyme A (acetyl-CoA), regulated, in part, by acetylation at lysine 635 (ACSS1-K635). We challenged our ACSS1 constitutive acetylation mimic knock-in (K635Q) mice by injecting a β3-adrenergic receptor agonist, CL-316243 (CL), to induce a thermogenic response. Strikingly, we show that Acss1K635Q/K635Q mice exhibit hypothermia and acute metabolic crisis following CL stimulus, as shown by significantly reduced oxygen consumption, carbon dioxide production, respiratory exchange ratio, and heat production. We also observed histological differences in both brown adipose tissue (BAT) and subcutaneous white adipose tissue (WAT), accompanied by altered expression and regulation of lipogenic enzymes and Uncoupling Protein 1 (UCP1) in Acss1K635Q/K635Q. In contrast to wild-type adipose tissues, Acss1K635Q/K635Q did not show changes in acetyl-CoA and acetate levels in response to CL, and mitochondria isolated from BAT displayed impaired respiration on palmitate. Lastly, beige adipocytes differentiated ex vivo from Acss1K635Q/K635Q mice showed altered response to the adenylate cyclase stimulator, forskolin, with unresponsive mitochondria and lipogenic lipid droplets, and lower fatty acid oxidation activity. These results suggest that non-acetylated ACSS1 plays an essential role in thermoregulation and the ability to metabolize free fatty acids.