Circumventing leptin resistance for weight control

Departments of Neuroscience and Physiology, College of Medicine, University of Florida McKnight Brain Institute, Gainesville, FL 32610-0244, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2001; 98(8):4279-81. DOI: 10.1073/pnas.091101498
Source: PubMed

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    • "Recent evidence indicates a role for leptin resistance and hyperleptinemia in the metabolic dysfunction that leads to diabetes [14]. Leptin resistance in the hypothalamic center can disrupt body weight regulation [15]. Leptin resistance in pancreatic beta cells can disrupt leptin suppression of insulin via the adipo-insular axis and promote hyperinsulinemia [16]. "
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    ABSTRACT: Established clinical tests are commonly used in disease diagnosis, but tools that enhance identification of metabolic dysfunctions are needed. This study was conducted to identify typical and atypical metabolite temporal patterns in response to paired meal challenge tests. Metabolic responses to high and low glycemic index (GI) meals were tested in 24 healthy pre-menopausal women, aged 20-50 y, with BMI of 25-30 kg/m2 using a cross-over design. On test days, blood glucose, insulin, leptin and non-esterified fatty acids were measured after an overnight fasting, and for 8 h following test meal consumption. The data were range scaled, and multivariate statistics were used to assess the presence of distinct response groups to the meal challenge tests. As expected, participants showed higher circulating glucose and insulin in response to the high GI compared to the low GI meal challenge. However, using range-scaling and Principal Component Analysis, three distinct groups were identified based on differential responses to the paired challenges. Members of the most populated group (n = 18) displayed little deviation from the expected response to the two meal challenges. Two minor groups (n = 3/group) with distinct responses were observed, one suggestive of sub-clinical insulin resistance, and the other suggestive of hyperleptinemia. The differential responses of glucose, insulin and leptin to low and high glycemic test meals revealed three response groups. Dietary intervention studies traditionally evaluate group responses, and aim to identify the overall effect in the population studied. In contrast, our study analyzed the variance in the meal challenge responses, using an integrated physiological approach, rather than a reductionist approach. This phenotyping approach may be useful for detecting subclinical metabolic dysfunctions, and it could contribute to improved personalized nutrition management. This study is registered in, record #200210295.
    Nutrition & Metabolism 03/2012; 9(1):26. DOI:10.1186/1743-7075-9-26 · 3.26 Impact Factor
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    • "The evidence that interruption of leptin-induced neural relays by either lesioning the VMN or surgical transection of descending hypothalamic tracts or deletion of leptin receptors in hypothalamic neurons lets on insulin hypersecretion preceding an increase in fat accretion and morbid obesity [20] [27] [35] [39] [46] [75], and intraventricular infusion of leptin suppressed blood insulin levels and increased receptor sensitivity prior to any discernable decrease in weight and adiposity endorses the involvement of central leptin receptors [31] [41] [56] [61] [76]. The possibility that centrally infused leptin in these paradigms may have leaked into the peripheral circulation in amounts sufficient to restrain insulin secretion directly from βcells , was ruled out by the observation that when leptin expression was increased locally in the hypothalamus, without leakage to the periphery it exerted a stable and pronounced suppression of blood insulin levels [1] [2] [9] [10] [23] [25] [36] [54]. "
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    ABSTRACT: Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans.
    Peptides 08/2009; 30(10):1957-63. DOI:10.1016/j.peptides.2009.07.021 · 2.62 Impact Factor
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    • "Collectively these studies suggest that CPAP improves OSA-induced leptin resistance and thus facilitates visceral fat loss. However, not all studies support a relationship between OSA severity and leptin levels (Schafer et al. 2002), and the role of leptin resistance in obesity (Caro et al. 1996; Kalra 2001; Schwartz et al. 1996), let alone in OSA, is still incompletely understood. Therefore, while there is no question that obesity is a cause of OSA, evidence that OSA can in turn affect obesity is circumstantial at best. "
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    ABSTRACT: There is increasing evidence of a causal relationship between sleep-disordered breathing and metabolic dysfunction. Metabolic syndrome (MetS), a cluster of risk factors that promote atherosclerotic cardiovascular disease, comprises central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, manifestations of altered total body energy regulation. Excess caloric intake is indisputably the key driver of MetS, but other environmental and genetic factors likely play a role; in particular, obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may induce or exacerbate various aspects of MetS. Clinical studies show that OSA can affect glucose metabolism, cholesterol, inflammatory markers, and nonalcoholic fatty liver disease. Animal models of OSA enable scientists to circumvent confounders such as obesity in clinical studies. In the most widely used model, which involves exposing rodents to IH during their sleep phase, the IH alters circadian glucose homeostasis, impairs muscle carbohydrate uptake, induces hyperlipidemia, and upregulates cholesterol synthesis enzymes. Complicating factors such as obesity or a high-fat diet lead to progressive insulin resistance and liver inflammation, respectively. Mechanisms for these effects are not yet fully understood, but are likely related to energy-conserving adaptations to hypoxia, which is a strong catabolic stressor. Finally, IH may contribute to the morbidity of MetS by inducing inflammation and oxidative stress. Identification of OSA as a potential causative factor in MetS would have immense clinical impact and could improve the management and understanding of both disorders.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 02/2009; 50(3):289-306. DOI:10.1093/ilar.50.3.289 · 2.39 Impact Factor
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