Molecular mechanisms of insulin resistance and the role of the adipocyte

Abstract

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFa a and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFa a in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFa a or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) signi®cantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and b b 3 -adrenoreceptor de®ciency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFb b production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFa a action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.

Systemic low-grade inflammation is related to both circulating and adipose tissue TNFα, leptin and IL-6 levels in obese women

“…19 Indeed, both IL-6 and TNFa are able to induce insulin resistance in adipose cells by inhibiting insulin signalling. 20,21 In addition to adipose tissue IL-6, TNFa and leptin content, we analysed PAI-1, another protein mainly released from human adipose tissue, 22 not considered as a stimulatory mediator of CRP synthesis by the liver. We found no correlation between both plasma and adipose tissue PAI-1 and circulating CRP levels.…”

Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance

“…[7][8][9] Their earlier studies focused on production of tumor necrosis factor-a (TNF-a) by adipose tissue and the ability of TNF-a to suppress signaling mediated by the insulin receptor (IR) and its substrates (IRSs). While the degree to which TNF-a itself mediates insulin resistance in humans is controversial, their findings clearly defined the potential for insulin resistance to be caused by cross-talk between inflammatory (TNF-a) and metabolic (IR/IRS) signaling cascades.…”

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

“…Excess fat has been shown to cause peripheral insulin resistance via multiple mechanisms which include among others, excess supply of non-esterified fatty acids [9], increased intracellular accumulation of muscle triglycerides and long chain acyl CoAs (LCACoAs) [9], excessive production of tumor necrosis factor-α [10], reduction in the concentration of adiponectin [11] and increased c-Jun amino-terminal kinase (JNK) activity [12].…”