There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.
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.
OBJECTIVE: Leptin, a primarily adipose tissue-derived protein product of the obesity (ob) gene, is an important regulator of energy metabolism. The strong association between body fat mass and elevated circulating leptin levels in humans suggests that leptin resistance, rather than leptin production, may contribute to the development of obesity and associated disorders. The purpose of this study is to evaluate the relationship between circulating plasma leptin levels and regulation of body weight over time among US men. DESIGN: Four-year prospective study. SUBJECTS: A total of 247 men from the Health Professionals Follow-up Study, who at baseline (1994), were 47 ± 64 y of age, were free of cardiovascular diseases, diabetes mellitus and malignant neoplasmas, and completed a detailed lifestyle questionnaire. In addition, all participants completed a follow-up questionnaire in 1998. MEASUREMENTS: Baseline plasma leptin levels and 4-y weight change. RESULTS: At the start of follow-up, men in the highest quintile for plasma leptin (mean 12.1 ngaml) weighed more, were less physically active, and had higher circulating insulin levels than men in the lowest quintile (mean 2.7 ngaml). After adjustments for baseline age, weight, height, smoking status, alcohol intake, and physical activity, each 10 ngaml increase in plasma leptin concentration was associated with a 1.68 kg (95% CI 0.14 ± 3.18 kg) weight gain over the 4-y follow-up period. The observed association between leptin level and weight gain was limited to men with a baseline body mass index (BMI) of ! 25 kgam 2 , in whom a 10ngaml higher baseline leptin was associated with a 2.45 kg (95% CI 0.73 ± 4.18-kg) weight gain. Further adjustments for baseline total energy intake, plasma insulin and soluble tumor necrosis factor receptors levels did not appreciably alter these results. Plasma insulin level was not independently associated with subsequent weight gain. CONCLUSION: These results suggest that elevated plasma leptin concentrations among overweight men may be a marker of leptin resistance and subsequent weight gain.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.