Futile cycle of β-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy

• DOI: 10.1016/j.bbalip.2022.159264
• Publication Date: 2022-12-17T01:44:46Z
• Authors: Adriano B. Chaves...; Albert S. Peixoto; Érique Castro; Tiago E. Oliveira; Luiz A. Perandini; Rafael J. Moreira; Railmara P. da Silva; Beatriz P. da Silva; Eduardo H. Moretti; Alexandre A. Steiner; Sayuri Miyamoto; Marcos Y. Yoshinaga; William T. Festuccia
• Keywords: Fatty Liver; Mice; 0303 health sciences; 03 medical and health sciences; Lipogenesis; Substrate Cycling; Animals; alpha-Linolenic Acid; Lipid Metabolism

Total absence of adipose tissue (lipoatrophy) is associated with the development of severe metabolic disorders including hepatomegaly and fatty liver. Here, we sought to investigate the impact of severe lipoatrophy induced by deletion of peroxisome proliferator-activated receptor gamma (PPARγ) exclusively in adipocytes on lipid metabolism in mice. Untargeted lipidomics of plasma, gastrocnemius and liver uncovered a systemic depletion of the essential linoleic (LA) and α-linolenic (ALA) fatty acids from several lipid classes (storage lipids, glycerophospholipids, free fatty acids) in lipoatrophic mice. Our data revealed that such essential fatty acid depletion was linked to increased: 1) capacity for liver mitochondrial fatty acid β-oxidation (FAO), 2) citrate synthase activity and coenzyme Q content in the liver, 3) whole-body oxygen consumption and reduced respiratory exchange rate in the dark period, and 4) de novo lipogenesis and carbon flux in the TCA cycle. The key role of de novo lipogenesis in hepatic steatosis was evidenced by an accumulation of stearic, oleic, sapienic and mead acids in liver. Our results thus indicate that the simultaneous activation of the antagonic processes FAO and de novo lipogenesis in liver may create a futile metabolic cycle leading to a preferential depletion of LA and ALA. Noteworthy, this previously unrecognized cycle may also explain the increased energy expenditure displayed by lipoatrophic mice, adding a new piece to the metabolic regulation puzzle in lipoatrophies.