Lustig RH, Sen S, Soberman JE, Velasquez-Mieyer PA. Obesity, leptin resistance, and the effects of insulin reduction. Int J Obes Relat Metab Disord 28, 1344-1348

Department of Pediatrics, University of California, San Francisco, CA 94143-0434, USA.
International Journal of Obesity (Impact Factor: 5). 10/2004; 28(10):1344-8. DOI: 10.1038/sj.ijo.0802753
Source: PubMed


Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>-3 kg/m(2)) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively with the change in REE:Leptin. These results suggest that the REE:Leptin ratio, while derivative, may serve as a useful clinical indicator of changes in leptin sensitivity within obese subjects. They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.

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    • "Neither were significant differences in body weight found in female offspring of moderate protein-restricted rats (30%) during gestation at the age of 24 weeks, although they did exhibit significantly greater food intake than their controls (Ikenasio-Thorpe et al., 2007). Central and peripheral resistance to insulin and/or leptin signaling have been proposed as important mechanisms responsible for the deregulation of energy homeostasis, which may lead to obesity (Levin and Dunn-Meynell, 2002; Lustig et al., 2004; Esteghamati et al., 2009; Palou et al., 2010a) (see below). On the other hand, adiponectin, which has been described as an important adipokine related with obesity and insulin sensitivity , may also play a role in the early programming mechanisms involved in the effects of gestational undernutrition, as it exerts important effects on carbohydrate metabolism, improving "
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    ABSTRACT: Epidemiological studies in humans and controlled intervention studies in animals have shown that nutritional programming in early periods of life is a phenomenon that affects metabolic and physiological functions throughout life. The phenotypes of health or disease are hence the result of the interaction between genetic and environmental factors, starting right from conception. In this sense, gestation and lactation are disclosed as critical periods. Continuous food restriction during these stages may lead to permanent adaptations with lasting effects on the metabolism of the offspring and may influence the propensity to develop different chronic diseases associated with obesity. However, the different outcomes of these adaptations on later health may depend on factors such as the type, duration, period, and severity of the exposure to energy restriction conditions, and they are, in part, gender specific. A better understanding of the factors and mechanisms involved in metabolic programming, and their effects, may contribute significantly to the prevention of obesity, which is considered to be one of the major health concerns of our time. Here, the different outcomes of maternal food restriction during gestation and lactation in the metabolic health of offspring, as well as potential mechanisms underlying these effects are reviewed.
    Full-text · Article · Nov 2012 · Frontiers in Physiology
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    • "Pancreatic islet mass, insulin production and body weight are inter-related [12], [18]. Insulin levels have been positively correlated with obesity in humans [19] and rodents [20]. Generally, obesity leads to higher demand for insulin production and the same is met by increase in beta cell mass. "
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    ABSTRACT: WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was downregulated in the mutant islets, over expression of WDR13 in the pancreatic beta cell line (MIN6) resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Given the higher insulin levels and better glucose clearance in Wdr13 gene deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "Central resistance to insulin and/or leptin has been proposed as important mechanisms responsible for the dysregulation of energy homeostasis, which may lead to obesity [15-17]. Here we show that the male and female offspring of dams that underwent moderate caloric restriction during gestation displayed higher circulating insulin levels than their controls; this occurred at a juvenile age, and previous to any apparent effect on body weight. "
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    ABSTRACT: We aimed to characterize the lasting effect of moderate caloric restriction during early pregnancy on offspring energy homeostasis, by focusing on the effects on food intake and body weight as well as on the insulin and leptin systems. Male and female offspring of 20% caloric restricted dams (from 1 to 12 days of pregnancy) (CR) and from control dams were studied. These animals were fed after weaning with a normal-fat (NF) diet until the age of 4 months, and then moved to a high-fat (HF) diet. Blood parameters were measured under fed and 14-h fasting conditions at different ages (2, 4 and 5 months). Food preferences were also assessed in adult animals. Accumulated caloric intake from weaning to the age of 5 months was higher in CR animals compared with their controls, and this resulted in higher body weight in adulthood in males, but not in females. Both male and female CR animals already showed higher insulin levels at the age of 2 months, under fed conditions, and higher HOMA-IR from the age of 4 months, compared with their controls. CR male animals, but not females, displayed higher preference for fat-rich food than their controls in adulthood and higher circulating leptin levels when they were under HF diet. It is suggested that hyperinsulinemia may play a role in the etiology of hyperphagia in the offspring of caloric restricted animals during gestation, with different outcomes on body weight depending on the gender, which could be associated with different programming effects on later leptin resistance.
    Full-text · Article · Aug 2010 · Nutrition & Metabolism
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