Acetyl-CoA and Metabolite Fluxes Regulate White Adipose Tissue Expansion

Abstract

White adipose tissue (WAT) depends on coordinated regulation of transcriptional and metabolic pathways to respond to whole-body energy demands. We highlight metabolites that contribute to biosynthetic reactions for WAT expansion. Recent studies have precisely defined how byproducts of carbohydrate and lipid metabolism affect physiological and endocrine functions in adipocytes. We emphasize the critical emerging roles of short-chain fatty acids (SCFAs) and tricarboxylic acid (TCA) cycle metabolites that connect lipogenesis to WAT energy balance and endocrine functions. These insights address how adipocytes use small molecules generated from central carbon metabolism to measure responses to nutritional stress.

Keywords: adipose tissue; insulin; lipid metabolism; metabolite; microenvironment.

Figure 1.. Adequate energy storage in WAT enables insulin sensitivity.

WAT is the primary storage location for lipids, with a coordinated uptake and release of fats. WAT from metabolically healthy lean or obese individuals resist the effects of the environment and expand appropriately in response to the anabolic actions of insulin (right). In the post-prandial setting, insulin suppresses free fatty acid release and guides the internalization of glucose from circulation. Insulin also acts to support balanced lipid uptake. Ultimately, lipid, glucose, and nutrients form the substrates for effective adipocyte differentiation and de novo lipogenesis. Overnutrition leads to WAT hypertrophy (left) and reduced insulin responsiveness. Hyperglycemia and hyperlipidemia ensue, coupled with local immune infiltration of mainly T cells and macrophages. Persistent inflammation disrupts insulin signaling in adipocytes and allows unmitigated lipolysis. This figure was created using  BioRender (https://biorender.com/).

Figure 2.. Metabolism of multiple substrates supports acetyl-CoA production in the fat cell.

Glycolysis converts glucose to pyruvate and lactate, providing pyruvate for the TCA cycle. In the mitochondria, pyruvate is converted to acetyl-CoA and enters the TCA cycle by combining with OAA to form citrate. Citrate export out of the mitochondria maintains the cytosolic acetyl-CoA pool needed for lipid synthesis and protein modifications. While providing reducing equivalents for OXPHOS and ATP production, the TCA cycle generates substrates for the biosynthesis of proteins, nucleotides, and lipids. Although glucose and fatty acid breakdown support mitochondrial acetyl-CoA production in adipocytes, carbon from amino acid sources also maintains the TCA cycle. Glutamine can serve as an anaplerotic substrate for the TCA cycle, providing a-KG and allowing preservation of the cycle in conditions of mitochondrial stress. BCAAs also represent anaplerotic sources in adipocytes, providing acetyl-CoA and succinyl-CoA to the TCA cycle. In Acly^+/+ adipocytes, glucose is the primary contributor to the cytosolic acetyl-CoA pool. However, adipocyte-specific deletion of ACLY reveals a compensatory pathway that requires ACSS2 to maintain the cytosolic acetyl-CoA pool. ACSS2 converts acetate derived from the gut microbiota or re-capture from the epigenome into acetyl-CoA for lipogenesis and protein modifications, including histone acetylation. Other short-chain fatty acids produced by gut microbiota promote histone acetylation by inhibiting histone deacetylases.