Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

Roth, Jonathan D.; Roland, Barbara; Cole, Rebecca L.; Trevaskis, James L.; Weyer, Christian; Koda, Joy E.; Anderson, Christen M.; Parkes, David G.; Baron, Alain

doi:10.1073/pnas.0706473105

Cited by 387 publications

(413 citation statements)

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“…The present studies extend emerging literature, where additive or synergistic interactions are reported for amylin in 32 and leptin), 40,41 to include small molecule agents that act via classic neurotransmitters. Consistent with the results reported here, co-administration of the amylin agonist pramlintide with sibutramine or phentermine in a clinical trial has recently been reported to result in increased weight loss in obese subjects.…”

Section: Discussionsupporting

confidence: 70%

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

Roth¹,

Trevaskis²,

Wilson³

et al. 2008

Int J Obes

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Objective: To characterize the interactive effects of amylin with phentermine or sibutramine on food intake, body weight/ composition and gene expression in diet-induced obese (DIO) rats. Design: DIO rats were intraperitoneally injected with a single dose of amylin (10 mg kg À1 ) and/or phentermine (1 mg kg À1 ) or chronically infused with amylin (100 mg kg À1 d À1 ) or vehicle with or without phentermine (0.5-10 mg kg À1 d À1 ) or sibutramine (3 mg kg À1 d À1 ) using two surgically implanted subcutaneous osmotic mini-pumps. Measurements: Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (amylin, phentermine or amylin þ phentermine). Body weight and composition (for amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (b-adrenergic receptors and uncoupling protein-1) were measured (for amylin and/or phentermine) after sustained infusion (2 weeks). Results: Acute co-administration of amylin (10 mg kg À1 ) and phentermine (1 mg kg À1 ) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain (B4-8%). Phentermine's anorexigenic (10-17%) and weightreducing effects (B0-5%) were only evident at the highest dose tested (10 mg kg À1 d À1 ). Combination of amylin (100 mg kg À1 d À1 ) and phentermine reduced food intake (30-43%), body weight (8-12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When amylin þ sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to amylin þ phentermine treatment, amylin þ sibutramine mediated weight loss was attributable to significant reductions in fat mass. Conclusions: Combined treatment of DIO rats with the pancreatic b-cell hormone amylin and phentermine or sibutramine resulted in additive anorexigenic, weight-and fat-reducing effects.

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Section: Discussionsupporting

confidence: 70%

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

Roth¹,

Trevaskis²,

Wilson³

et al. 2008

Int J Obes

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“…It is known that a co-infusion of amylin and leptin reduces body weight and adiposity synergistically in DIO prone rats [22]. Additionally, it has been shown that peripheral administration of amylin restores leptin sensitivity in obese rats and humans [33]. These findings suggest that an interaction exists between exogenous amylin and the prevailing circulating leptin values.…”

Section: Amylin-induced Suppression Of Energy Intake Is Decreased Aftmentioning

confidence: 56%

“…Furthermore, because of the known interaction between amylin and leptin [22,33], we determined whether an increase of amylin, independent of obesity, alters circulating leptin levels. Again we observed that as circulating amylin levels increased, there was a trend toward a decrease in leptin levels.…”

Section: Hyperamylinemia Alone Does Not Cause Amylin Insensitivitymentioning

confidence: 99%

Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin

Boyle¹,

Rossier²,

Lutz³

2011

Physiology & Behavior

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Obesity results in the increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin; increased circulating levels of pancreatic amylin have also been described in obese humans and rodents. Because leptin-resistance is present in diet-induced obese (DIO) rats, and because hyperleptinemia seems necessary for the full development of leptin resistance, we tested whether amylin sensitivity is inversely correlated with adiposity, such that DIO reduces the anorectic action of acute amylin. We also determined if hyperamylinemia leads to a change in amylin sensitivity. In the first experiment, rats were chronically exposed to a high fat (HF; 60% fat) diet or fed standard chow for control. The anorectic response to amylin was tested on several occasions over a 14 week observation period. HF feeding led to the expected increase in body adiposity; the response to an acute amylin injection (5-50 g/kg s.c.) was unaltered for 10 weeks of HF feeding. Even after 12 weeks on a HF diet, which clearly caused obesity, acute administration of amylin (5 g/kg, s.c.) was still able to suppress food intake, although the suppression was not statistically significant. Further experiments using additional doses of amylin will be necessary to demonstrate possible amylin resistance after HF feeding or in DIO rats. In the second experiment, we tested more specifically whether hyperamylinemia that may result from HF feeding and subsequent obesity, reduces the sensitivity of the amylin signaling system. To avoid confounding factors, we chronically infused lean chow fed rats with amylin (5 or 10 g/kg/day s.c.) to elevate their plasma amylin concentration to levels observed in obese rats (30-40 pM). In the absence of obesity, hyperamylinemia did not lead to a reduced sensitivity to acute amylin (5-20 g/kg s.c.) injections; acute amylin reduced eating similarly in all groups of rats. Overall, we concluded that direct diet effects by short term exposure to HF appear to be of little importance for amylin sensitivity; further, long-term maintenance on a HF diet and the resulting obesity only slightly attenuated the anorectic response to acute amylin. Because we observed no marked changes in amylin sensitivity in lean, chow fed rats with induced hyperamylinemia, amylin receptor downregulation in chronic hyperamylinemia does not seem to occur. 1 Long-term maintenance on a HF diet only slightly attenuates acute amylin action.2 Attenuation of amylin action seems more related to obesity than HF exposure.3 Acute amylin sensitivity is not reduced by chronic hyperamylinemia.3 ABSTRACTObesity results in the increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin; increased circulating levels of pancreatic amylin have also been described in obese humans and rodents. Because leptinresistance is e.g. present in diet-induced obese (DIO) rats, and because hyperleptinemia seems necessary for the full development of leptin resistance, we tested whether amyl...

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“…Interestingly, recent studies suggest that amylin interacts with leptin, possibly at the level of the VMH and the Arc. Amylin pretreatment partially restored hypothalamic leptin sensitivity in leptin resistant diet-induced obese rats in the VMH (Roth et al, 2008) and increased leptin sensitivity also in lean rats (Turek et al, 2010). These effects have been suggested to depend on polysynaptic connections from the AP to the VMH and the Arc (Roth et al, 2008;Turek et al, 2010).…”

Section: Functional Considerationsmentioning

confidence: 99%

“…Amylin pretreatment partially restored hypothalamic leptin sensitivity in leptin resistant diet-induced obese rats in the VMH (Roth et al, 2008) and increased leptin sensitivity also in lean rats (Turek et al, 2010). These effects have been suggested to depend on polysynaptic connections from the AP to the VMH and the Arc (Roth et al, 2008;Turek et al, 2010). Our demonstration of very dense projections from the amylin-activated LPB region to the VMH and the Arc (Supplementary Results and Fig.…”

Section: Functional Considerationsmentioning

confidence: 99%

Identification of central projections from amylin-activated neurons to the lateral hypothalamus

2010

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The ability of the pancreatic hormone amylin to inhibit food intake relies on a direct activation of the area postrema (AP). This activation is synaptically transmitted to the nucleus of the solitary tract (NTS), the lateral parabrachial nucleus (LPB), the central amygdaloid nucleus (Ce) and the lateral bed nucleus of stria terminalis (BSTL). Interestingly, neurons of the rostro-dorsal lateral hypothalamic area (dLHA), which are activated during fasting, are inhibited by peripheral amylin, although they lack amylin receptors. Using the retrograde tracer cholera toxin-B (Ctb) we analyzed whether the dLHA receives neuronal projections from amylin-activated brain areas. The anterograde tracer biotinylated dextran-amine (BDA) was used to confirm the projections and to identify further neuronal pathways potentially involved in amylin signaling. We identified dense projections from the amylin activated neurons in the LPB and sparse projections from the NTS to the dLHA. LPB fiber efferents were found in close proximity to dLHA nuclei activated by 24h of fasting. The AP and the Ce showed no projections to the dLHA. Dense efferents were also observed from the LPB to other hypothalamic areas, namely to the ventromedial, dorsomedial, paraventricular and arcuate nuclei. This study provides neuroanatomical evidence that among the amylin activated areas, the LPB provides the strongest input to the dLHA, thus it may mediate the amylin-induced inhibition of the dLHA. ABSTRACTThe ability of the pancreatic hormone amylin to inhibit food intake relies on a direct

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Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

Cited by 387 publications

References 40 publications

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin

Identification of central projections from amylin-activated neurons to the lateral hypothalamus

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