Contributions of adipocyte lipid metabolism to body fat content and implications for the treatment of obesity

Abstract

Obesity is a chronic disease that increases susceptibility to various diseases, particularly cardiovascular dysfunction, type 2 diabetes, and some types of cancer. In this review, we highlighted recent evidence in mouse models that support a potential benefit of increasing adipose lipid utilization through stimulating lipolysis in adipose tissue and fatty acid oxidation. Brown adipocyte development within white adipose tissue of humans suggests that mouse models may be applicable to human obesity. Consequently, new therapies should target adipose tissue to specifically reduce fat mass through controlled triglyceride utilization.

Figure 1

(A) Post-pandrial increase in insulin leads to induction of lipogenesis and inhibition of lipolysis. Lipoprotein lipase (LPL) is the rate-limiting enzyme for the import of triglyceride-derived fatty acids from VLDL or chylomicrons for storage by the adipose tissue. Uptake of free fatty acids (FFA) involves passive diffusion through the lipid bilayer or protein-facilitated transfer. Within the adipocytes, FA are activated into acyl-CoA and 3 acyl-CoA are esterified with glycerol to form triglycerides (TG) stored into the lipid droplet. Additionally, insulin triggers glucose and amino acid (AA) transport into adipocytes that are metabolized into acetyl-CoA. ACC (Acetyl-CoA carboxylase) which converts acetyl-CoA to malonyl-CoA is the commited step of FA synthesis pathway. Leptin antagonizes lipogenesis and promotes lipolysis. (B) In some situations, white adipocytes can acquire brown adipocytes features and lipid stores are mobilized. Sequential breakdown of intracellular TG (lipolysis) provides FA and glycerol. Diglyceride formation (DG) is catalysed by HSL and ATGL, DG are hydrolysed by HSL and monoglyceride catabolizing involve MGL. Insulin and leptin have opposing action on lipolysis. FA and glycerol can be liberated in the circulation or FA can be oxidized in mitochondria. Fatty acid oxidation (FAO) forms substrates for the respiratory chain (RESP). ATP or heat can be produced by the discharge of the intermembrane space proton gradient via the ATP synthase or UCP, respectively. Leptin has been shown to exert direct and indirect stimulation in FAO. Abbreviations: CoA: coenzyme A, Glycerol-P: phospho-glycerol, PERA: perilipin A, GLUT: glucose transporter, VLDL: very low density lipoprotein, N: nucleus, ATGL: adipose triglyceride lipase, HSL: hormone sensitive lipase, MGL: monoglyceride lipase, DG: diglyceride, MG: monoglyceride, UCP: uncoupling protein, ATP-S: ATP-synthase, .