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Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

Key Points

  • Insulin resistance due to obesity is a primary event in the development of type 2 diabetes. Recent work indicates a central role of adipose tissue dysfunction in linking obesity to insulin resistance.

  • Fatty acids and their derivatives are mediators of insulin resistance in skeletal muscle, probably through deleterious effects on the insulin signalling pathway. Increased exposure of skeletal muscle tissue to elevated fatty acids in rodents and humans impairs insulin-stimulated glucose uptake.

  • The impaired ability of adipose tissue to sequester fatty acids in triglyceride stores results in increasing fatty acid concentrations in the circulation and the exposure of skeletal muscle to these high fatty acid levels. This impairment of adipose function can be caused by a chronic inflammatory state that arises within adipose tissue in obese animals and humans.

  • Inflammatory cytokines, including tumour-necrosis factor-α (TNFα), have profound effects on adipocyte metabolism by impairing triglyceride synthesis and storage, and promoting the hydrolysis and release of triglycerides as free fatty acids. These effects are mediated in part through downregulation of the key adipocyte transcription factor PPARγ (peroxisome proliferator-activated receptor-γ).

  • Recent data implicate lipid-droplet proteins, including newly described CIDE family proteins, in the promotion of triglyceride storage and as significant targets of PPARγ regulation. Through effects on these proteins, downregulation of PPARγ can mediate diminished lipid storage ability of inflamed adipose tissue. Expression of these proteins may be determinants of the differential ability to sequester fat away from the circulation and the propensity of obese humans to develop insulin resistance.

Abstract

Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.

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Figure 1: Chronic inflammation in adipose tissue triggers insulin resistance in skeletal muscle.
Figure 2: Chronic inflammation impairs triglyceride deposition in adipose tissue.
Figure 3: PPARγ downregulation by TNFα impairs triglyceride storage in adipose cells.
Figure 4: TNFα decreases triglyceride deposition and increases lipolysis in adipose cells.
Figure 5: TNFα downregulates lipid-droplet proteins and enhances lipolysis in adipose cells.

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Acknowledgements

We thank the members of our laboratory group for excellent discussions on the issues addressed here. We acknowledge funding for our studies covered here by the National Institutes of Health (grants DK030648 and DK030898), including the University of Massachusetts Medical School Diabetes and Endocrinology Research Center (DK32520).

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Glossary

White adipose tissue

The predominant fat storage tissue in animals, consisting mostly of adipocytes but also other cell types such as mast cells and macrophages. It is distributed in a number of subcutaneous and visceral depots.

Free fatty acid

A carboxylic acid with aliphatic chains of 4–28 carbons, which can be esterified with glycerol to form triglycerides, the main stored form of lipid.

Acipimox

A nicotinic-acid analogue that reduces plasma and intracellular fatty acid levels by suppressing lipolysis.

Adipokine

A cytokine or hormone that is secreted by adipose tissue.

Lipodystrophy

Abnormality of the adipose tissue that is associated with total or partial loss of body fat. This might have a genetic origin in humans or occur as a result of other diseases.

MAP4K4

(Mitogen-activated protein kinase kinase kinase kinase-4). A mammalian Ser/Thr protein kinase related to Saccharomyces cerevisiae Sterile-20 (STE20).

Omental adipose tissue

The fat depot found within the peritoneum, in close association with the stomach and other internal organs.

Diacylglycerol

A molecule that consists of two fatty acid chains esterified with glycerol, produced by the cleavage of membrane phosphatidylinositol 4,5-bisphosphate. Diacylglycerol functions as a signalling molecule by activating protein kinase C.

Salicylates

A group of derivatives of salicylic acid, including aspirin and acetylsalicylic acid, which are widely used as analgesics and anti-inflammatory medications.

Toll-like receptors

Cell-surface receptors that recognize a wide variety of molecules, primarily markers of foreign organisms including bacteria. Main functions include the activation of the innate immune response in infection.

Sphingolipids

Lipids that consist of the aliphatic alcohol sphingosine linked to a fatty acid chain and a variety of head groups. Sphingolipids include ceramides, sphingomyelin and glycosphingolipids.

Glucocorticoids

Steroid hormones, including cortisol, that are produced in the adrenal gland. These hormones have potent effects on energy metabolism in the liver, fat and elsewhere.

C/EBPα

(CCAAT/enhancer-binding protein-α). A transcription factor that has a key role in the differentiation of adipocytes.

Adrenoreceptors

A class of G-protein-coupled receptors activated by catecholamines. Adrenoreceptors in white fat stimulate lipolysis in response to catecholamines.

Catecholamines

A group of amine hormones including adrenaline and noradrenaline. These are produced by the adrenal gland in response to starvation and other stresses.

Perilipin

A main protein component of adipocyte lipid droplets, which surrounds the lipids and participates in the regulation of lipolysis.

Rosiglitazone

An antidiabetic drug, one of several thiazolidinediones (TZDs) used therapeutically. Many TZDs are known to be high-affinity ligand activators of PPARγ.

HOMA-IR

(Homeostatic model assessment of insulin resistance). An estimation of the degree of insulin resistance that is calculated from clinical measurement of fasting blood glucose and insulin levels.

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Guilherme, A., Virbasius, J., Puri, V. et al. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 9, 367–377 (2008). https://doi.org/10.1038/nrm2391

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