The role of leptin in leptin resistance and obesity

Research Service, Department of Veterans Affairs Medical Center, Gainesville, FL 32608, USA.
Physiology & Behavior (Impact Factor: 2.98). 07/2006; 88(3):249-56. DOI: 10.1016/j.physbeh.2006.05.038
Source: PubMed


Although the presence of hyperleptinemia with leptin resistance and obesity has long been recognized, a causal role of elevated leptin in these biological states remains unclear. This article summarizes some recent work from our laboratory supporting the concept that leptin, in and of itself, promotes leptin resistance and such resistance compounds the metabolic impact of diet-induced obesity. Results from multiple studies demonstrate that (1) chronically elevated central leptin decreases hypothalamic leptin receptor expression and protein levels and impairs leptin signaling; (2) leptin resistance and obesity are associated with reduced leptin receptors and diminished maximal leptin signaling capacity; and (3) leptin resistance confers increased susceptibility to diet-induced obesity. In essence, the augmented leptin accompanying obesity contributes to leptin resistance, and this leptin resistance promotes further obesity, leading to a vicious cycle of escalating metabolic devastation.

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    • "(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) more and more leptin, leading to a vicious cycle and in some cases, to the development of obesity [5] [32]. "
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    ABSTRACT: Obesity is often associated with leptin resistance, which leads to a physiological system with high leptin concentration but unable to respond to leptin signals and to regulate food intake. We propose a mathematical model of the leptin-leptin receptors system, based on the assumption that leptin is a regulator of its own receptor activity, and investigate its qualitative behavior. Based on current knowledge and previous models developed for body weight dynamics in rodents, the model includes the dynamics of leptin, leptin receptors and the regulation of food intake and body weight. It displays two stable equilibria, one representing a healthy state and the other one an obese and leptin resistant state. We show that a constant leptin injection can lead to leptin resistance and that a temporal variation in some parameter values influencing food intake can induce a change of equilibrium and a pathway to leptin resistance and obesity. Copyright © 2015. Published by Elsevier Inc.
    Mathematical biosciences 06/2015; 267. DOI:10.1016/j.mbs.2015.06.008 · 1.30 Impact Factor
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    • "Despite methodological differences, there is little evidence for an association between leptin and dementia-related outcomes in elderly adults who are obese or have a large waist circumference. This is hypothesized to reflect an acquired resistance to the central effects of leptin, though this remains poorly understood [25] [26] [27]. Given the inconsistent findings for normal weight and overweight elderly adults, further research is needed to address this. "
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    ABSTRACT: Background: US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. Objective: To investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. Methods: We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests A and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. Results: The multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73-0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail-Making Tests A (RR = 0.85, 95% CI 0.71-1.02) and B (RR = 0.90, 0.79-1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. Conclusions: High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians.
    Journal of Alzheimer's disease: JAD 12/2014; 44(4). DOI:10.3233/JAD-141836 · 4.15 Impact Factor
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    • "Leptin is anorexigenic, and as such, is part of a negative feedback system that decreases appetite as fat stores grow [16], [20], [21]. Deregulation of this system leads to obesity through several known mechanisms [22]–[25]. "
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    ABSTRACT: High-fructose diets have been implicated in obesity via impairment of leptin signaling in humans and rodents. We investigated whether fructose-induced leptin resistance in mice could be used to study the metabolic consequences of fructose consumption in humans, particularly in children and adolescents. Male C57Bl/6 mice were weaned to a randomly assigned diet: high fructose, high sucrose, high fat, or control (sugar-free, low-fat). Mice were maintained on their diets for at least 14 weeks. While fructose-fed mice regularly consumed more kcal and expended more energy, there was no difference in body weight compared to control by the end of the study. Additionally, after 14 weeks, both fructose-fed and control mice displayed similar leptin sensitivity. Fructose-feeding also did not change circulating glucose, triglycerides, or free fatty acids. Though fructose has been linked to obesity in several animal models, our data fail to support a role for fructose intake through food lasting 3 months in altering of body weight and leptin signaling in mice. The lack of impact of fructose in the food of growing mice on either body weight or leptin sensitivity over this time frame was surprising, and important information for researchers interested in fructose and body weight regulation.
    PLoS ONE 09/2014; 9(9):e107206. DOI:10.1371/journal.pone.0107206 · 3.23 Impact Factor
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