Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity

Wilsey, Jared; Zolotukhin, Sergei; Prima, Victor; Scarpace, Philip J.

doi:10.1152/ajpregu.00193.2003

Cited by 61 publications

(74 citation statements)

References 25 publications

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“…At death, hypothalamic pSTAT3 levels were elevated with age and with HF feeding in both young and aged rats (Tables 3 and 4). This is consistent with previous reports where HF feeding increased hypothalamic pSTAT3 levels compared to chow-fed controls (Wilsey et al 2003). More interestingly, whereas AM251 treatment raised pSTAT3 levels in both young and aged chow-fed rats, it only reached significance in aged rats (Tables 3 and 4).…”

Section: Biochemical Indicatorssupporting

confidence: 94%

Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding

Judge

Zhang²,

Scarpace

2009

Journal of Endocrinology

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Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and agerelated, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.

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Section: Biochemical Indicatorssupporting

confidence: 94%

Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding

Judge

Zhang²,

Scarpace

2009

Journal of Endocrinology

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“…In the present study, in the face of pharmacological stimulation with exogenous leptin, the maximal signalling capacity, as measured by P-STAT3 transcription factor binding to DNA, was reduced in the leptinresistant lean rats compared with the leptin-responsive lean rats. This phenomenon is similar to that described in dietinduced obese and leptin-resistant rodents, where basal leptin signal transduction is elevated [18] yet maximal signalling capacity following exogenous central leptin stimulation is diminished [12]. Potentially, the leptin-induced leptin resistance may be linked directly to the impaired maximal leptin signalling capacity.…”

Section: Discussionsupporting

confidence: 78%

“…Typically, high-fat feeding is characterised by an initial increase in energy consumption. A homeostatic response is then initiated that restores energy intake to pretreatment or nearly pretreatment levels [18]. Our lean, leptin-induced leptin-resistant rats apparently lack this homeostatic response, and as a result, following high-fat feeding, the energy consumption is maintained at an elevated level above that of the control high-fat-fed animals.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2005

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Aims/hypothesis: Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats. Materials and methods: Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344×BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 μg leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined. Results: The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptinresistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls. Conclusions/interpretation: The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity.

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“…Previous work has reported leptin resistance in the arcuate nucleus of Sprague-Dawley rats fed a HF diet for 12 wk (36). This suggests that leptin resistance in VAN may occur prior to leptin resistance in VAN.…”

Section: Discussionmentioning

confidence: 84%

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Lartigue

Serre

Espero

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

154

142

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de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab 301: E187-E195, 2011. First published April 26, 2011; doi:10.1152/ajpendo.00056.2011.-Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.lipopolysaccharide; high-fat diet; suppressor of cytokine signaling-3 THE GUT PLAYS A CRUCIAL ROLE in sensing luminal contents that is important for the efficient digestion and absorption of ingested nutrients but also in integration of other physiological processes that regulate metabolism and energy expenditure, such as pancreatic ␤-cell function, hepatic function, and also food intake (34). In response to the presence or absence of food, enteroendocrine cells of the gut release anorexic or orexigenic hormones, respectively. The first site of integration of these signals occurs at the level of vagal afferent neurons (VAN), which project to and stimulate second-order neurons in the dorsal vagal complex of the hindbrain (27). VAN express receptors for many of the anorexigenic and orexigenic hormones released from the gut wall and mediate changes in gastrointestinal function and food intake in response to luminal nutrients (18).Leptin is a gut and adipose tissue-derived hormone that regulates a range of biological functions and processes, including energy intake and expenditure, body fat, neuroendocrine systems...

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Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity

Cited by 61 publications

References 25 publications

Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding

Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding

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

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

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