Acyl‐CoA Synthetase‐isoform 1 (ACSL1) is essential for FA oxidation in adipose tissue: lessons from adipose‐specific knockout of ACSL1

Abstract

Long chain acyl‐CoA synthetase (ACSL) catalyses the conversion of fatty acids into their acyl‐CoA derivatives. ACSL1, one of five ACSL isoforms, is highly expressed in white and brown adipose tissue where it was thought to be important for triacylglycerol formation. To investigate the role of ACSL1 in adipose tissue we created an adipose‐specific knockout of ACSL1, the ACSL1A‐/− mouse. Although we expected these mice to have a reduced ability to store fatty acids as triacylglycerol in adipose, compared to control mice (ACSL1flox/flox) when fed a low‐fat diet, subcutaneous and visceral fat depot mass was 30% higher in ACSL1A‐/− mice, and when fed a diet containing 45% kcal fat, weight gain was similar. In mature adipocytes isolated from ACSL1A‐/− mice, the rate of fatty acid oxidation was 50% lower, suggesting a role for ACSL1 in FA oxidation rather than TAG synthesis. ACSL1A‐/− mice were cold intolerant with body temperature dropping below 30°C within 2‐5 h in a 4°C environment. ACSL1A‐/− mice had reduced oxygen consumption in response to adrenergic stimuli but had intact cold‐stimulated transcriptional expression of PGC‐1α and UCP1 in brown adipose tissue, showing that adrenergic signaling was intact. The reduced FA oxidation in white adipocytes, together with the cold intolerance of the ACSL1A‐/− mice, strongly indicates that ACSL1 activates fatty acids destined for oxidation.Grant Funding SourceAHA‐Pre‐doctoral Fellowship Mid‐Atlantic Affiliate