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.
Highlights
Insulin signalling and its impairment in obesity and type 2 diabetes is a vast field that commands the full attention of Diabetologia (2013) 56:949–964 many hundreds of laboratories worldwide
Two pathways stimulated by insulin contribute to the pool of fatty acids that is esterified into triacylglycerol in adipocytes: fatty acid uptake from circulating triacylglycerol and de novo fatty acid synthesis
Another major regulatory pathway of triacylglycerol synthesis involves the ability of glucose to increase the activity of ChREBPα, which promotes the expression of lipogenic genes [21]
Summary
Insulin signalling and its impairment in obesity and type 2 diabetes is a vast field that commands the full attention of Diabetologia (2013) 56:949–964 many hundreds of laboratories worldwide. For many of the most interesting findings, separating fact from fiction will take years for confirmatory studies to be reported and controversies resolved These realities create a huge challenge for scientists trying to understand insulin signalling mechanisms and their dysfunctions in metabolic disease, especially for those who are just entering the field. One approach to this scientific challenge is to focus on a small but critical corner of the puzzle. We focus in this review on insulin signalling and its dysfunctions in relation to adipocyte triacylglycerol sequestration, recognising this topic's broader implications for understanding the pathophysiology of obesity and type 2 diabetes
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