ACSL1 multi‐tissue knockout mice are resistant to diet‐and age‐induced obesity and insulin resistance

Long chain acyl‐CoA synthetase 1 (ACSL1) is the major activator of long‐chain fatty acids in heart and adipose tissue. In order to understand the functional role of ACSL1, we studied mice with a temporally‐induced knockout of ACSL1 in multiple tissues (Acsl1 T−/− ), including heart, skeletal muscle, kidney, and white adipose. Compared to littermate controls (tamoxifen‐injected ACSL1 flox/flox ), lack of ACSL1 caused 80–90% lower oxidation of palmitate in heart and adipose. Compared to controls, hearts that lacked ACSL1 took up 75% less [1‐ 14 C]bromopalmitate and 10‐fold more 2‐[ 14 C]deoxyglucose. Compared to controls, chow‐fed Acsl1 T−/− mice had higher rates of glycogen degradation in liver and heart. When fed a high fat diet (HFD; 45% of kcal from lard and soybean oil), ACSL1 T−/− male mice failed to become obese. HFD‐fed ACSL1 T−/− and control mice had similar food intake, respiratory quotients and heat production, but ACSL1 T−/− mice were significantly more active at night. HFD‐fed control mice had abnormal glucose and insulin tolerance tests, whereas HFD‐fed ACSL1 T−/− mice maintained normal whole‐body insulin sensitivity. With aging, 14‐month old chow‐fed ACSL1 T−/− female mice also had a lower fat mass and better glucose tolerance than controls. Thus, ACSL1 T−/− mice were protected from HFD‐and age‐induced obesity and insulin resistance.