The therapeutic potential of leptin

Proietto, Joseph; Thorburn, Anne W.

doi:10.1517/eoid.12.3.373.21480

Cited by 10 publications

(11 citation statements)

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“…In patients with BED, where an increase in leptin production occurred because of their enhanced fat stores, one would expect decreased rather than enhanced plasma levels of AEA. In most cases, however, our BED patients were truly obese and, hence, likely characterized by reduced sensitivity to abnormally high circulating leptin levels (Proietto and Thorburn, 2003). Therefore, it is possible that impaired leptin levels or signalling, which was not observed in our BN patients, may explain why higher levels of AEA were found in subjects with BED and AN, but not in those with BN.…”

Section: Discussionmentioning

confidence: 77%

Blood Levels of the Endocannabinoid Anandamide are Increased in Anorexia Nervosa and in Binge-Eating Disorder, but not in Bulimia Nervosa

Monteleone

Matías

Martiadis

et al. 2005

Neuropsychopharmacol

243

149

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The endocannabinoid system, consisting of two cannabinoid receptors (CB 1 and CB 2 ) and the endogenous ligands anandamide (arachidonoylethanolamide (AEA)) and 2-arachidonoylglycerol (2-AG), has been shown to control food intake in both animals and humans, modulating either rewarding or quantitative aspects of the eating behavior. Moreover, hypothalamic endocannabinoids seem to be part of neural circuitry involved in the modulating effects of leptin on energy homeostasis. Therefore, alterations of the endocannabinoid system could be involved in the pathophysiology of eating disorders, where a deranged leptin signalling has been also reported. In order to verify this hypothesis, we measured plasma levels of AEA, 2-AG, and leptin in 15 women with anorexia nervosa (AN), 12 women with bulimia nervosa (BN), 11 women with binge-eating disorder (BED), and 15 healthy women. Plasma levels of AEA resulted significantly enhanced in both anorexic and BED women, but not in bulimic patients. No significant change occurred in the plasma levels of 2-AG in all the patients' groups. Moreover, circulating AEA levels were significantly and inversely correlated with plasma leptin concentrations in both healthy controls and anorexic women. These findings show for the first time a derangement in the production of the endogenous cannabinoid AEA in drug-free symptomatic women with AN or with BED. Although the pathophysiological significance of this alteration awaits further studies to be clarified, it suggests a possible involvement of AEA in the mediation of the rewarding aspects of the aberrant eating behaviors occurring in AN and BED.

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Section: Discussionmentioning

confidence: 77%

Blood Levels of the Endocannabinoid Anandamide are Increased in Anorexia Nervosa and in Binge-Eating Disorder, but not in Bulimia Nervosa

Monteleone

Matías

Martiadis

et al. 2005

Neuropsychopharmacol

243

149

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“…However, with dietinduced obesity, even though leptin levels rise proportionally with adiposity, these elevated leptin levels fail to prevent weight gain (33). Such reduced response or unresponsiveness to the metabolic effects of endogenous or exogenous leptin is described as leptin resistance, and is characteristic of both obese humans (12,28) and rodents (19,40). Moreover, our experimental models of leptin resistance in rats suggest that such leptin resistance not only prevents the metabolic responses to leptin but also is one cause of obesity, including 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

267

217

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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.

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“…In contrast, leptin therapy in obese humans with elevated leptin has proven to be futile, presumably because of pronounced leptin resistance, and this approach has been mostly abandoned (15). Leptin resistance thus is generally considered as a hindrance to pharmacological treatment for obesity, and little attention has been paid to its potential role in abnormal body weight homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

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

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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...

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The therapeutic potential of leptin

Cited by 10 publications

References 0 publications

Blood Levels of the Endocannabinoid Anandamide are Increased in Anorexia Nervosa and in Binge-Eating Disorder, but not in Bulimia Nervosa

Blood Levels of the Endocannabinoid Anandamide are Increased in Anorexia Nervosa and in Binge-Eating Disorder, but not in Bulimia Nervosa

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

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