Rahmouni K, Morgan DA, Morgan GM, Mark AL, Haynes WG. Role of selective leptin resistance in diet-induced obesity hypertension

Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States
Diabetes (Impact Factor: 8.1). 08/2005; 54(7):2012-8. DOI: 10.2337/diabetes.54.7.2012
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Leptin is an adipocyte-derived hormone that plays a key role in the regulation of body weight through its actions on appetite and metabolism. Leptin also increases sympathetic nerve activity (SNA) and blood pressure. We tested the hypothesis that diet-induced obesity is associated with resistance to the metabolic actions of leptin but preservation of its renal SNA and arterial pressure effects, leading to hypertension. Mice were fed a high-fat diet for 10 weeks to induce moderate obesity. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular leptin was significantly attenuated in the obese mice. Regional SNA responses to leptin were differentially altered in diet-induced obese mice. Renal SNA response to leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated in obese mice. Radiotelemetric arterial pressure was approximately 10 mmHg higher in obese mice. Furthermore, the increase in arterial pressure in response to long-term (12 days) leptin treatment was preserved in obese mice. Thus, mice with diet-induced obesity exhibit circulating hyperleptinemia and resistance to the metabolic actions of leptin. However, there is preservation of the renal sympathetic and arterial pressure responses to leptin, which represent a potential mechanism for the adverse cardiovascular consequences of obesity.

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    • "Consistent with our previous findings, leptin caused significant increases in both renal and lumbar SNA in mice (Rahmouni et al. 2005b; Morgan et al. 2008). However , the sympathetic nerve activation induced by leptin was comparable whether the mice were anesthetized or conscious. "
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    ABSTRACT: The adipocyte-derived hormone, leptin, has emerged as an important regulator of regional sympathetic nerve activity (SNA) with pathophysiological implications in obesity. Genetically engineered mice are useful to understand the molecular pathways underlying the SNA responses evoked by leptin. However , so far the effect of leptin on direct SNA in mice has been studied under general anesthesia. Here, we examined the sympathetic responses evoked by leptin in conscious mice. Mice were instrumented, under ketamine/xylazine anesthesia, with renal or lumbar SNA recordings using a thin (40 gauge) bipolar platinum–iridium wire. The electrodes were exteriorized at the nape of the neck and mice were allowed (5 h) to recover from anesthesia. Interestingly , the reflex increases in renal and lumbar SNA caused by sodium nitro-prusside (SNP)-induced hypotension was higher in the conscious phase versus the anesthetized state, whereas the increase in both renal and lumbar SNA evoked by leptin did not differ between anesthetized or conscious mice. Next, we assessed whether isoflurane anesthesia would yield a better outcome. Again, the SNP-induced increase in renal SNA and baroreceptor-renal SNA reflex were significantly elevated in the conscious states relative to isoflurane-anesthetized phase, but the renal SNA response induced by leptin in the conscious states were qualitatively comparable to those evoked above. Thus, despite improvement in sympathetic reflexes in conscious mice the sympathetic responses evoked by leptin mimic those induced during anesthesia.
    09/2015; 3(9). DOI:10.14814/phy2.12554
    • "(2015), in adulthood (Samuelsson et al., 2010). This is unlikely to be due to impaired central leptin signalling, as maternal obesity-mediated programming of leptin resistance is hypothalamic nuclei-specific (Kirk et al., 2009) and diet-induced obesity in adulthood does not impair central leptin-mediated sympathetic activity via the renal nerve (Rahmouni et al., 2005). Therefore it has been postulated that the hyperleptinaemia seen in adult offspring of maternal obesity animal models drives the accompanying hypertension via the concomitant increase in central activation of the sympathetic nervous system (Samuelsson et al., 2010; Simonds et al., 2014). "
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    ABSTRACT: Obesity in women of child-bearing age is a growing problem in developed and developing countries. Evidence from human studies indicates that maternal BMI correlates with offspring adiposity from an early age and predisposes to metabolic disease in later life. Thus the early life environment is an attractive target for intervention to improve public health. Animal models have been used to investigate the specific physiological outcomes and mechanisms of developmental programming that result from exposure to maternal obesity in utero. From this research, targeted intervention strategies can be designed. In this review we summarise recent progress in this field, with a focus on cardiometabolic disease and central control of appetite and behaviour. We highlight key factors that may mediate programming by maternal obesity, including leptin, insulin and ghrelin. Finally, we explore potential lifestyle and pharmacological interventions in humans and the current state of evidence from animal models. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 07/2015; DOI:10.1016/j.yhbeh.2015.06.015 · 4.63 Impact Factor
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    • "In this review, we focus on the cardiorespiratory actions of leptin. Leptin circulates freely in the plasma and crosses the blood–brain barrier via a saturable receptor-mediated transport system [65] to enter into the central nervous system centers (CNS) where it regulates neural pathways that control appetite [36], sympathetic nerve activity (SNA) and thermogenesis [60] [76]. In addition, it has been suggested that leptin stimulates chemorespiratory responses [5–7,44]. "
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    ABSTRACT: Leptin, a peptide hormone produced by adipose tissue, acts in brain centers that control critical physiological functions including metabolism, breathing and cardiovascular function. The importance of leptin for respiratory control is evident by the fact that leptin deficient mice exhibit impaired ventilatory responses to carbon oxide (CO2), which can be corrected by intracerebroventricular leptin replacement therapy. Leptin is also recognized as an important link between obesity and hypertension. Humans and animal models lacking either leptin or functional leptin receptors exhibit many characteristics of the metabolic syndrome, including hyperinsulinemia, insulin resistance, hyperglycemia, dyslipidemia and visceral adiposity, but do not exhibit increased sympathetic nerve activity (SNA) and have normal to lower blood pressure (BP) compared to lean controls. Even though previous studies have extensively focused on the brain sites and intracellular signaling pathways involved in leptin effects on food intake and energy balance, the mechanisms that mediate the actions of leptin on breathing and cardiovascular function are only beginning to be elucidated. This mini-review summarizes recent advances on the effects of leptin on cardiovascular and respiratory control with emphasis on the neural control of respiratory function and autonomic activity. Copyright © 2015. Published by Elsevier Inc.
    Life Sciences 01/2015; 125. DOI:10.1016/j.lfs.2015.01.019 · 2.70 Impact Factor
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