Although saturated and monounsaturated very-long-chain fatty acids (VLCFAs) have long been associated with undesirable effects on health, including obesity, heart failure, and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20-C24 saturated and monounsaturated VLCFAs mainly in liver, brown and white adipose tissue, and triglyceride-rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue, and resistance against diet-induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation that is associated with reduced de novo fatty acid synthesis and uptake. As a consequence, the VLDL-triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin, and increased expression of orexigenic peptides in the hypothalamus, the Elovl3(-/-) mice do not compensate by increased food intake. Thus, these results reveal that C20-C22 saturated and monounsaturated VLCFAs produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake, and storage in adipose tissue.
The Elovl3 gene belongs to the Elovl gene family, which encodes for enzymes involved in the elongation of very long chain fatty acids. The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue on cold exposure. Here we show that hepatic Elovl3 mRNA expression follows a distinct diurnal rhythm exclusively in mature male mice, with a sharp increase early in the morning Zeitgeber time (ZT) 20, peaks around ZT2, and is back to basal level at the end of the light period at ZT10. In female mice and sexually immature male mice, the Elovl3 expression was constantly low. Fasting and refeeding mice with chow or high-fat diet did not alter the Elovl3 mRNA levels. However, animals that were exclusively fed during the day for 9 d displayed an inverted expression profile. In addition, we show that Elovl3 expression is transcriptionally controlled and significantly induced by the exposure of the synthetic glucocorticoid dexamethasone. Taken together, these data suggest that Elovl3 expression in mouse liver is under strict diurnal control by circulating steroid hormones such as glucocorticoids and androgens. Finally, Elovl3 expression was found to be elevated in peroxisomal transporter ATP-binding cassette, subfamily D(ALD), member 2 ablated mice and suppressed in ATP-binding cassette subfamily D(ALD) member 2 overexpressing mice, implying a tight cross talk between very long chain fatty acid synthesis and peroxisomal fatty acid oxidation.
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