Our laboratory previously reported that
lecithin:cholesterol acyltransferase (LCAT) and
LDL receptor double knock-out mice (Ldlr(-/-)xLcat(-/-) or DKO) spontaneously develop functioning ectopic brown adipose tissue (BAT) in skeletal muscle, putatively contributing to protection from the diet-induced
obesity phenotype. Here we further investigated their developmental origin and the mechanistic role of
LCAT deficiency. Gene profiling of skeletal muscle in DKO newborns and adults revealed a classical lineage. Primary quiescent satellite cells (SC) from chow-fed DKO mice, not in Ldlr(-/-)xLcat(+/+) single-knock-out (SKO) or C57BL/6 wild type, were found to (i) express exclusively classical BAT-selective genes, (ii) be primed to express key functional BAT genes, and (iii) exhibit markedly increased ex vivo adipogenic differentiation into brown adipocytes. This gene priming effect was abrogated upon feeding the mice a 2% high
cholesterol diet in association with accumulation of excess intracellular
cholesterol. Ex vivo
cholesterol loading of chow-fed DKO SC recapitulated the effect, indicating that cellular
cholesterol is a key regulator of SC-to-BAT differentiation. Comparing adipogenicity of Ldlr(+/+)xLcat(-/-) (LCAT-KO) SC with DKO SC identified a role for
LCAT deficiency in priming SC to express BAT genes. Additionally, we found that reduced cellular
cholesterol is important for adipogenic differentiation, evidenced by increased induction of adipogenesis in
cholesterol-depleted SC from both LCAT-KO and SKO mice. Taken together, we conclude that ectopic BAT in DKO mice is classical in origin, and its development begins in utero. We further showed complementary roles of
LCAT deficiency and cellular
cholesterol reduction in the SC-to-BAT adipogenesis.