Insulin action in adipocytes, adipose remodeling, and systemic effects

Abstract

On this 100^th anniversary of the discovery of insulin, we recognize the critical role that adipocytes, which are exquisitely responsive to insulin, have played in determining the mechanisms for insulin action at the cellular level. Our understanding of adipose tissue biology has evolved greatly, and it is now clear that adipocytes are far more complicated than simple storage depots for fat. A growing body of evidence documents how adipocytes, in response to insulin, contribute to the control of whole-body nutrient homeostasis. These advances highlight adipocyte plasticity, heterogeneity, and endocrine function, unique features that connect adipocyte metabolism to the regulation of other tissues important for metabolic homeostasis (e.g., liver, muscle, pancreas).

Figure 1.

1A. Insulin-regulated pathways in adipocytes. See text for detailed discussion. The dotted arrow from insulin receptor signifies that signal transduction cascade from the receptor to Rab10 and control of lipolysis involves multiple signaling intermediaries. In control of GLUT4 we highlight Rab10 because that is the only protein along the pathway discussed in the text. GLUT4= Glucose transporter type 4; Rab10= Ras-related protein 10; FFAs= free fatty acids; TG=triglycerides; DNL=de novo lipogenesis; ChREBP= Carbohydrate-responsive element-binding protein; Acetyl-CoA= acetyl coenzyme A. 1B. Insulin action in white adipose tissue (WAT) alters fuel metabolism in liver and muscle via inter-tissue communication. Insulin signaling in adipocytes suppresses WAT lipolysis, decreasing the flux of free fatty acids (FFAs) and glycerol to the liver, and thereby contributing to the suppression of hepatic glucose production (HGP). FFAs, once converted to acetyl CoA, act as positive allosteric modulators of pyruvate carboxylase (PC), the enzyme catalyzing the first step of hepatic gluconeogenesis. Glycerol is a gluconeogenic substrate. The reduced flux of these metabolites to the liver contributes to the reduction in liver glucose output in the fed state. HGP is also regulated by direct action of insulin to promote hepatic glycogen synthesis and by the effect of glucagon and other counter-regulatory hormones on glycogenolysis. Insulin exerts an anti-lipolytic effect in WAT which maintains insulin sensitivity in muscle by reducing the availability of fatty acids and their derivatives. In addition, insulin promotes de novo lipogenesis in WAT, indirectly by stimulating glucose transport through GLUT4 which activates the lipogenic transcription factor, ChREBP. This results in synthesis and secretion of metabolically beneficial signaling lipids which increase muscle insulin sensitivity. Adipocytes also synthesize and release adipo-cytokines which alter metabolism in liver and muscle. The role of insulin in the regulation of adipo-cytokines needs further investigation. Black arrows indicate insulin direct effects, green arrows indicate insulin indirect effects. GLUT4= Glucose transporter type 4; ChREBP= Carbohydrate-responsive element-binding protein; Acetyl-CoA= acetyl coenzyme A; PC= pyruvate carboxylase.

Figure 1.

1A. Insulin-regulated pathways in adipocytes. See text for detailed discussion. The dotted arrow from insulin receptor signifies that signal transduction cascade from the receptor to Rab10 and control of lipolysis involves multiple signaling intermediaries. In control of GLUT4 we highlight Rab10 because that is the only protein along the pathway discussed in the text. GLUT4= Glucose transporter type 4; Rab10= Ras-related protein 10; FFAs= free fatty acids; TG=triglycerides; DNL=de novo lipogenesis; ChREBP= Carbohydrate-responsive element-binding protein; Acetyl-CoA= acetyl coenzyme A. 1B. Insulin action in white adipose tissue (WAT) alters fuel metabolism in liver and muscle via inter-tissue communication. Insulin signaling in adipocytes suppresses WAT lipolysis, decreasing the flux of free fatty acids (FFAs) and glycerol to the liver, and thereby contributing to the suppression of hepatic glucose production (HGP). FFAs, once converted to acetyl CoA, act as positive allosteric modulators of pyruvate carboxylase (PC), the enzyme catalyzing the first step of hepatic gluconeogenesis. Glycerol is a gluconeogenic substrate. The reduced flux of these metabolites to the liver contributes to the reduction in liver glucose output in the fed state. HGP is also regulated by direct action of insulin to promote hepatic glycogen synthesis and by the effect of glucagon and other counter-regulatory hormones on glycogenolysis. Insulin exerts an anti-lipolytic effect in WAT which maintains insulin sensitivity in muscle by reducing the availability of fatty acids and their derivatives. In addition, insulin promotes de novo lipogenesis in WAT, indirectly by stimulating glucose transport through GLUT4 which activates the lipogenic transcription factor, ChREBP. This results in synthesis and secretion of metabolically beneficial signaling lipids which increase muscle insulin sensitivity. Adipocytes also synthesize and release adipo-cytokines which alter metabolism in liver and muscle. The role of insulin in the regulation of adipo-cytokines needs further investigation. Black arrows indicate insulin direct effects, green arrows indicate insulin indirect effects. GLUT4= Glucose transporter type 4; ChREBP= Carbohydrate-responsive element-binding protein; Acetyl-CoA= acetyl coenzyme A; PC= pyruvate carboxylase.

Figure 2

A. Adipose tissue remodeling in normal physiology and pathophysiology. Adipocytes undergo rapid and reversible morphologic changes in the transition between fasting and fed state. Upon food ingestion, adipocytes expand to store excess fuel including circulating lipids and glucose, as triglycerides (TG) in the lipid droplet. This is accompanied by altered secretion of lipids, cytokines and other adipokines. Adipocytes can expand by two different mechanisms: hypertrophy (increase in size) and hyperplasia (increase in number). Once the expansion limit is reached, adipocytes become dysfunctional. Chronic overnutrition is associated with hypertrophic adipocytes presenting crown-like structures which contain necrotic cells and macrophages. Aberrant adipose tissue remodeling with chronic overnutrition is accompanied by immune cell recruitment and activation, hypoxia, fibrosis. Figure 2B. Insulin effects on glucose and lipid metabolism in functional and dysfunctional adipocytes (Left panel) Healthy adipocytes are sensitive to the metabolic actions of insulin. (Right panel) Overloaded or dysfunctional adipocytes are resistant to many actions of insulin. This has consequences for ectopic lipid accumulation in other tissues. Dysfunctional adipocytes also have reduced secretion of lipo-cytokines which have beneficial metabolic effects and increased secretion of detrimental proteins and lipids which exert adverse effects in other organs.