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

Shapiro, Alexandra; Matheny, Michael; Zhang, Yi; Tümer, Nihal; Cheng, Kit‐Yan; Rogrigues, Enda; Zolotukhin, Sergei; Scarpace, Philip J.

doi:10.2337/db07-0863

Cited by 31 publications

(50 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When these rats are then exposed to a high-fat diet, they gain more weight and adiposity compared with weightmatched, leptin-responsive, high-fat fed counterparts (31). Conversely, if rats are first fed a high-fat diet and then chronically exposed to elevated central leptin (resulting in leptin resistance), such rats also gain greater body weight and adiposity compared with their high-fat fed counterparts without leptin resistance (34). Collectively, these data indicate that leptin resistance increases the susceptibility for diet-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding

Shapiro¹,

Mu²,

Roncal³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

267

217

View full text Add to dashboard Cite

RJ, Scarpace PJ. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol 295: R1370 -R1375, 2008. First published August 13, 2008 doi:10.1152/ajpregu.00195.2008.-It has been suggested that increased fructose intake is associated with obesity. We hypothesized that chronic fructose consumption causes leptin resistance, which subsequently may promote the development of obesity in response to a high-fat diet. Sprague-Dawley rats were fed a fructose-free control or 60% fructose diet for 6 mo and then tested for leptin resistance. Half of the rats in each group were then switched to high-fat diet for 2 wk, while the other half continued on their respective diets. Chronic fructose consumption caused leptin resistance, while serum leptin levels, weight, and adiposity were the same as in control rats that were leptin responsive. Intraperitoneal leptin injections reduced 24-h food intake in the fructose-free group (73.7 Ϯ 6.3 vs. 58.1 Ϯ 8 kcal, P ϭ 0.02) but had no effect in fructose-fed rats (71.2 Ϯ 6.6 vs. 72.4 Ϯ 6.4 kcal, P ϭ 0.9). Absence of anorexic response to intraperitoneal leptin injection was associated with 25.7% decrease in hypothalamic signal transducer and activator of transcription 3 phosphorylation in the high-fructose-fed rats compared with controls (P ϭ 0.015). Subsequent exposure of the fructose-mediated, leptin-resistant rats to a high-fat diet led to exacerbated weight gain (50.2 Ϯ 2 g) compared with correspondingly fed leptin-responsive animals that were pretreated with the fructose-free diet (30.4 Ϯ 5.8 g, P ϭ 0.012). Our data indicate that chronic fructose consumption induces leptin resistance prior to body weight, adiposity, serum leptin, insulin, or glucose increases, and this fructose-induced leptin resistance accelerates highfat induced obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding

Shapiro¹,

Mu²,

Roncal³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

267

217

View full text Add to dashboard Cite

show abstract

“…instance, rats rendered leptin resistant by chronic elevation of leptin (18), a combination of HF feeding and elevated leptin (24), or chronic dietary consumption of fructose (25) subsequently exhibit exacerbated weight and adiposity gain on a HF diet compared with their respective HF-fed leptin-responsiveness controls, suggesting that leptin resistance, in and of itself, is one causative factor in obesity.…”

Section: Discussionmentioning

confidence: 99%

Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis

Matheny

Zhang²,

Shapiro³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

We used recombinant adenoassociated virus (rAAV)-mediated gene delivery to overexpress a mutant of rat leptin yielding a protein that acts as a neutral leptin receptor antagonist. The long-term consequences of this overexpression on body weight homeostasis and physical activity, as assessed by voluntary wheel running (WR), were determined in F344 ϫ Brown Norway (BN) rats. Leptin antagonist overexpression was confirmed by examination of mRNA levels in the hypothalamus. Food consumption and body weight gain were exacerbated in the antagonist group during both chow and high-fat feeding periods over the 192-day experiment. In a second experiment, a lower dose of antagonist vector was used that resulted in no change in food consumption but still increased body weight. The degree of antagonist overexpression was sufficient to partially block signal transducer and activator of transcription 3 (STAT3) phosphorylation due to administration of an acute submaximal dose of leptin. Rats were provided free access to running wheels for 4 days during both the chow and high-fat feeding periods. With both antagonist doses and during both chow and high-fat feeding, WR was substantially less with antagonist overexpression. In contrast, when leptin was overexpressed in the hypothalamus, WR activity was increased by greater than twofold. At death, adiposity and serum leptin levels were greater in the antagonist group. These data indicate that submaximal central leptin receptor blockade promotes obesity and diminishes WR activity. These findings underscore the critical role of unrestrained leptin receptor activity in long-term energy homeostasis and suggest that even minor disruption of leptin receptor function can promote obesity. leptin resistance; gene therapy; high-fat feeding; voluntary wheel running AT THE TIME OF ITS DISCOVERY, the adipocyte-derived hormone leptin sparked great interest as a potential therapy for obesity (1, 10). The interest in this compound has waned because of the reduced efficacy and sensitivity of leptin in obese humans (15) and animals (22). Although of questionable therapeutic potential, leptin is an essential hormone for maintaining energy homeostasis. Nowhere is this more evident than in the overt obesity phenotypes resultant from the absence of leptin or leptin receptors due to genetic mutations (9,10,27). Extensive studies in animals with normal genetic background have documented the potent role of leptin in regulating feeding and energy expenditure. These studies invariably involve introduction of exogenous leptin. On the other hand, it is more challenging to evaluate the importance of endogenous leptin and leptin receptor activity in long-term body weight homeostasis. Such knowledge is pivotal for understanding the role of leptin in body weight homeostasis and obesity prevention. Long-term leptin receptor blockade would be one approach to tackle this important issue.Evolutionary pressure has resulted in redundancy in both anorexic and orexigenic pathways to preserve and regulate energy stores in or...

show abstract

“…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).…”

mentioning

confidence: 97%

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interaction Between Exercise and Leptin in the Treatment of Obesity

Morrison

2008

Diabetes

View full text Add to dashboard Cite

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...

show abstract

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

Cited by 31 publications

References 39 publications

Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding

Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding

Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis

Interaction Between Exercise and Leptin in the Treatment of Obesity

Contact Info

Product

Resources

About