Insulin signalling mechanisms for triacylglycerol storage

Abstract

Insulin signalling is uniquely required for storing energy as fat in humans. While de novo synthesis of fatty acids and triacylglycerol occurs mostly in liver, adipose tissue is the primary site for triacylglycerol storage. Insulin signalling mechanisms in adipose tissue that stimulate hydrolysis of circulating triacylglycerol, uptake of the released fatty acids and their conversion to triacylglycerol are poorly understood. New findings include (1) activation of DNA-dependent protein kinase to stimulate upstream stimulatory factor (USF)1/USF2 heterodimers, enhancing the lipogenic transcription factor sterol regulatory element binding protein 1c (SREBP1c); (2) stimulation of fatty acid synthase through AMP kinase modulation; (3) mobilisation of lipid droplet proteins to promote retention of triacylglycerol; and (4) upregulation of a novel carbohydrate response element binding protein β isoform that potently stimulates transcription of lipogenic enzymes. Additionally, insulin signalling through mammalian target of rapamycin to activate transcription and processing of SREBP1c described in liver may apply to adipose tissue. Paradoxically, insulin resistance in obesity and type 2 diabetes is associated with increased triacylglycerol synthesis in liver, while it is decreased in adipose tissue. This and other mysteries about insulin signalling and insulin resistance in adipose tissue make this topic especially fertile for future research.

Docosahexaenoic Acid–Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties

“…The systemic effects of WAT largely reflect its role in the control of blood lipid levels, as well as in the secretion of numerous bioactive peptides (e.g., adiponectin, leptin) from WAT cells (5,6). Adipocytes also release lipid-based mediators such as branched fatty acid esters of hydroxy fatty acids (FAHFAs) (7) and palmitoleate (8), which could improve local and whole-body glucose metabolism (9,10). Moreover, FAHFA administration also stimulated glucagon-like peptide 1 and insulin secretion, and reduced obesity-associated WAT inflammation in mice through cell surface G-protein-coupled receptor 120-dependent signaling (7).…”

A causal role for hyperinsulinemia in obesity

“…The acute increase in circulating insulin induced by food intake promotes nutrient storage in its major peripheral target tissues, primarily by stimulating: (1) glucose uptake in adipose tissue and muscle; (2) glycolysis and glycogen synthesis in muscle and liver; (3) lipogenesis in adipose tissue and liver and (4) protein synthesis in muscle and liver. Conversely, insulin has repressive functions on glycogenolysis, lipolysis and protein breakdown, as well as gluconeogenesis and ketogenesis in the liver (Taniguchi et al 2006, Cheng et al 2010, Czech et al 2013. Insulin may also exert local autocrine effects to promote beta-cell growth and survival, as well as influence its own production and secretion ( Fig.…”

“…Biochemical studies have shown that insulin plays key roles in regulating white adipocyte lipid accumulation, by inhibiting lipolysis as well as promoting fatty acid uptake and triglyceride synthesis (lipogenesis) and also by stimulating the expression of genes involved in lipid uptake and storage (Kersten 2001, Czech et al 2013 (Fig. 2).…”

“…It seems that certain stages of life, such as the perinatal period and adolescence, are particularly Insulin acts through multiple mechanisms to stimulate lipid uptake and storage and to inhibit lipid breakdown. Additional details have been expertly reviewed by Czech et al (2013).…”

Human Adipocytes : Proteomic Approaches

“…Insulin-dependent inhibition of lipolysis is mediated through PKB catalyzed phosphorylation and activation of cGMP-inhibited 3´,5´-cyclic phosphodiesterase B (PDE3B) [44] and perhaps also through downregulation of lipolytic gene transcription via inhibition of forkhead box protein O1 (FoxO1) [45] (Figure 3). …”