Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

Scarpace, Philip J.; Matheny, Michael; Tümer, Nihal; Cheng, Kit‐Yan; Zhang, Y.

doi:10.1007/s00125-005-1763-x

Cited by 80 publications

(74 citation statements)

References 27 publications

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“…In a previous study, the Scarpace lab demonstrated that when lean rats were subjected to chronic leptin overexpression, the initial decrease in body weight waned over time in association with a reduction in leptin sensitivity. When these rats were then placed on a high-fat diet, they displayed an enhanced diet-induced hyperphagia and weight gain (7). Together with the current work, these experiments indicate that by inducing leptin resistance, chronic hyperleptinemia attenuates the ability to resist diet-induced obesity.…”

supporting

confidence: 68%

Interaction Between Exercise and Leptin in the Treatment of Obesity

Morrison

2008

Diabetes

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Recent data indicate that roughly 32% of the U.S. population is obese and an additional 34% is overweight (1). Considering the physical, psychological, and physiological complications associated with obesity, developing approaches to reduce these numbers is of critical importance. The identification of leptin as a hormonal link between energy stores and the brain inspired a renewed focus on the study of energy balance and contributed to the description of a neuronal network that mediates the metabolic regulation of feeding behavior, reproduction, glucose homeostasis, immune function, bone formation, lipid metabolism, etc. But for all its promise, much of the initial enthusiasm over leptin has waned with the realization that obese individuals respond rather poorly to leptin treatment and manifest a syndrome of leptin resistance. Although leptin may not be the anti-obesity treatment initially hoped for, there may yet be life to the leptin story. Just as progress has been made in defining and overcoming insulin resistance, considerable effort has focused on developing approaches to overcome leptin resistance. In this issue of Diabetes, Shapiro et al.(2) provide evidence that modest exercise synergizes with leptin treatment to markedly reduce body weight in individuals made obese by a high-fat diet, even though neither reduce body weight alone.The importance of leptin in energy balance is illustrated by the extreme obese phenotype induced by leptin deficiency, and by the dramatic reduction in food intake and body weight that occurs upon treatment of this condition with leptin. While leptin levels are closely matched to body adiposity at steady state, negative energy balance produces a fall in leptin levels that is more rapid than the change in body adiposity. Preventing this fall is sufficient to attenuate many of the physiological events associated with negative energy balance, and it is widely agreed that leptin is a critical signal of weight loss. However, is the opposite also true? That is, does increased leptin serve as a signal of positive energy balance? Though the answer to this question is unclear, there is increasing evidence that enhancing leptin sensitivity produces a lean, obesity-resistant phenotype (3-6). These observations therefore suggest that leptin may indeed act to prevent weight gain, and that enhancing leptin sensitivity might be beneficial in the fight against obesity.The work by Shapiro et al. (2) builds upon previous experiments by the Scarpace group. This work demonstrates not only that prolonged leptin overexpression is ineffective at reducing body weight in obese rats, but also that chronic leptin treatment actually worsens diet-induced obesity (2,7). Far from providing a cure, chronic hyperleptinemia might actually contribute to obesity. But why would increased leptin levels make matters worse? First, it is important to note that the effect only occurs in animals on a high-fat diet, as those rats on a low-fat diet exhibited the expected leptin-induced reduction in body weight. Second, i...

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supporting

confidence: 68%

Interaction Between Exercise and Leptin in the Treatment of Obesity

Morrison

2008

Diabetes

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“…We have observed similar results when leptin is centrally overexpressed in lean rats. When such rats are provided a high-fat diet, they display exacerbated weight and adiposity gain compared with high-fat-fed control rats [39]. Moreover, we have demonstrated that blockade of the leptin receptor aggravates the dietary weight gain [40].…”

Section: Discussionmentioning

confidence: 72%

Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness

Zhang

Cheng

et al. 2007

Diabetologia

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Aims/hypothesis Central pro-opiomelanocortin (Pomc) gene therapy ameliorates genetic-or age-related obesity. We hypothesised that this treatment would delay or prevent dietary obesity in young, lean rats. Materials and methods Recombinant adeno-associated virus encoding Pomc (rAAV-Pomc) was delivered bilaterally into the basomedial hypothalamus of lean rats for 42 days. Food intake, body weight, serum hormones, brown adipose tissue (BAT) uncoupling protein 1 (UCP1) and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed. Beginning on day 43, half of the rats remained on chow while the others received a high-fat diet for 89 days. We examined energy balance and responsiveness to the melanocortin agonist melanotan II (MTII) or the antagonist SHU9119. Results Pomc gene delivery produced elevated hypothalamic Pomc mRNA (fourfold) and α-melanocyte-stimulating hormone levels in the arcuate nucleus (twofold). Food intake and body weight were not altered by rAAV-Pomc in rats fed standard-chow. In rAAV-Pomc rats at day 42, perirenal fat and serum leptin decreased but overall visceral adiposity did not; expression of the hypothalamic agouti-related protein (Agrp) mRNA was elevated, whereas expression of melanocortin 3 and 4 receptor mRNA was reduced; BAT UCP1 protein increased nearly fourfold. The rAAV-Pomc rats fed the high-fat diet consumed more energy and gained more body weight compared with chow-or high-fat-fed controls that did not receive Pomc gene delivery. The anorexic response to MTII was impaired, whereas the orexigenic effect of SHU9119 was enhanced by rAAV-Pomc pretreatment. Conclusions/interpretation Delivery of the Pomc gene alters energy homeostasis in lean rats, predisposing them to dietinduced obesity. Diminished hypothalamic melanocortin receptors, increased Agrp expression, and potential rewiring of brain circuits may underlie the exacerbated obesity.

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“…Such leptin-induced, leptinresistant lean rats exhibited an exacerbated weight and adiposity gain on a high-fat diet compared with their respective high-fat-fed controls (3,4). Hence, leptin resistance promotes dietary obesity in lean rodents.…”

Section: Discussionmentioning

confidence: 98%

“…Leptin treatment exerts potent responses in lean rodents, producing impressive weight and fat loss (2) but is generally ineffective in rats that have diet-induced obesity due to high-fat feeding and, consequently, that are leptin resistant (3)(4)(5). The presence of this leptin resistance constitutes a major obstacle in curtailing diet-induced weight gain (6,7), and one approach to treat obesity would be to restore leptin actions or circumvent the leptin resistance in dietary obese animals.…”

mentioning

confidence: 99%

Synergy Between Leptin Therapy and a Seemingly Negligible Amount of Voluntary Wheel Running Prevents Progression of Dietary Obesity in Leptin-Resistant Rats

et al. 2008

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OBJECTIVE-We examined whether chronic leptin treatment of diet-induced obese rats promotes or alleviates the susceptibility to continued high-fat feeding. Second, we examined if voluntary wheel running is beneficial in reducing the trajectory of weight gain in high-fat-raised leptin-resistant rats.RESEARCH DESIGN AND METHODS-Sprague-Dawley rats were fed a standard diet or a high-fat diet for 5 months, and then hypothalamic leptin overexpression was induced through central administration of adeno-associated virus-encoding leptin while continuing either the standard or high-fat diet. Two weeks later, half of the rats in each group were provided access to running wheels for 38 days while being maintained on either a standard or high-fat diet.RESULTS-In standard diet-raised rats, either wheel running or leptin reduced the trajectory of weight gain, and the combined effect of both treatments was additive. In high-fat-raised leptinresistant rats, leptin overexpression first transiently reduced weight gain but then accelerated the weight gain twofold over controls. Wheel running in high-fat-raised rats was sixfold less than in standard diet-raised rats and did not affect weight gain. Surprisingly, wheel running plus leptin completely prevented weight gain. This synergy was associated with enhanced hypothalamic signal transducer and activator of transcription (STAT) 3 phosphorylation and suppressor of cytokine signaling 3 expression in wheel running plus leptin compared with leptin-treated sedentary high-fat counterparts. This enhanced STAT3 signaling associated with the combination treatment occurred only in high-fat-raised, leptin-resistant rats and not in standard dietraised, leptin-responsive rats. T he adipocyte-derived hormone leptin acts in the brain to reduce food intake and stimulate energy expenditure (1). Leptin treatment exerts potent responses in lean rodents, producing impressive weight and fat loss (2) but is generally ineffective in rats that have diet-induced obesity due to high-fat feeding and, consequently, that are leptin resistant (3-5). The presence of this leptin resistance constitutes a major obstacle in curtailing diet-induced weight gain (6,7), and one approach to treat obesity would be to restore leptin actions or circumvent the leptin resistance in dietary obese animals. CONCLUSIONS-ChronicExercise, one time-honored treatment for obesity, has proven beneficial in humans. Exercise reduces body weight and decreases visceral adiposity in overweight patients (8) who presumably possess some degree of leptin resistance. The beneficial effects of exercise are generally believed to be derived mostly through increased energy expenditure. A recent study (9) indicated that a single bout of exercise enhances brain leptin signaling and short-term leptin responses in leptin-sensitive rats. Although chronic exercise exerts a positive impact on obese rodents in terms of weight regulation (10), this issue has not been addressed from the perspective of leptin resistance and/or leptin responsiveness. Thus, we h...

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Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

Cited by 80 publications

References 27 publications

Interaction Between Exercise and Leptin in the Treatment of Obesity

Interaction Between Exercise and Leptin in the Treatment of Obesity

Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness

Synergy Between Leptin Therapy and a Seemingly Negligible Amount of Voluntary Wheel Running Prevents Progression of Dietary Obesity in Leptin-Resistant Rats

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