Synergy between amylin and cholecystokinin for inhibition of food intake in mice

Bhavsar, Sunil; Watkins, Justin; Young, Andrew

doi:10.1016/s0031-9384(98)00110-3

Cited by 115 publications

(78 citation statements)

References 26 publications

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“…[28][29][30] Intermeal interval is governed by a complex cascade of post-ingestive, neural, endocrine and metabolic signals. In rodents, amylin has also been shown to synergize with at least two signals (CCK 31 and PYY ) 32 Co-administration of amylin and phentermine JD Roth et al neurohormonal signals is unknown, but could contribute to amylin þ phentermine protraction of the intermeal interval. The generation of plasma hormonal profiles in amylin þ phentermine-treated rats before and after the consumption of a meal, and/or the assessment of food intake in the context of a sham feeding preparation may aid in our understanding of these potential mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Salmon calcitonin and the amylinergic control of food intake appear to be mediated by central mechanisms. For instance, although exogenously administered amylin and sCT both reduce gastric emptying (6,16,34,43,44), this action does not appear to fully account for their satiety effects. A comparison of intravenous doses of amylin or sCT has shown a similar dose range that reduces meal sizes, also inhibits gastric emptying (33,34).…”

Section: Discussionmentioning

confidence: 99%

Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys

Bello

Kemm

Moran³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Although studies of the molecular determinants of preproexendin-4 processing have not yet been reported, the finding of detectable levels of circulating exendin-4 in MT-exendin transgenic mice is consistent with the correct processing and secretion of the lizard preproexendin precursor in murine tissues in vivo. Furthermore, the levels of circulating bioactive exendin-4 detected in MT-exendin-4 transgenic mice are clearly much higher than plasma levels of less potent GLP-1 (1) and are certainly within the range of or higher than the plasma levels of exendin-4 noted to decrease blood glucose in diabetic db/db mice (11,40). Hence, the findings observed in our studies cannot simply be attributable to a failure to achieve sufficient levels of bioactive exendin-4 in vivo.…”

Section: Discussionmentioning

confidence: 99%

Sustained Expression of Exendin-4 Does Not Perturb Glucose Homeostasis, β-Cell Mass, or Food Intake in Metallothionein-Preproexendin Transgenic Mice

Baggio

Adatia

Bock

et al. 2000

Journal of Biological Chemistry

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Activation of glucagon-like peptide (GLP)-1 receptor signaling promotes glucose lowering via multiple mechanisms, including regulation of food intake, glucose-dependent insulin secretion, and stimulation of ␤-cell mass. As GLP-1 exhibits a short t1 ⁄2 in vivo, the biological consequences of prolonged GLP-1 receptor signaling remains unclear. To address this question, we have now generated metallothionein promoter-preproexendin (MT-Ex) transgenic mice. MT-Ex mice process preproexendin correctly, as is made evident by detection of circulating plasma exendin-4 immunoreactivity using high pressure liquid chromatography and an exendin-4-specific radioimmunoassay. Despite elevated levels of exendin-4, fasting plasma glucose and glucose clearance following oral and intraperitoneal glucose tolerance tests are normal in MT-Ex mice. Induction of transgene expression significantly reduced glycemic excursion during both oral and intraperitoneal glucose tolerance tests (p < 0.05) and increased levels of glucose-stimulated insulin following oral glucose administration (p < 0.05). Despite evidence that exendin-4 may induce ␤-cell proliferation, ␤-cell mass and islet histology were normal in MT-Ex mice. MT-Ex mice exhibited no differences in basal food intake or body weight; however, induction of exendin-4 expression was associated with reduced short term food ingestion (p < 0.05). In contrast, short term water intake was significantly reduced in the absence of zinc in fluid-restricted MT-Ex mice (p < 0.05). These findings illustrate that sustained elevation of circulating exendin-4 is not invariably associated with changes in glucose homeostasis, increased ␤-cell mass, or reduction in food intake in mice in vivo.Glucagon-like peptide-1 (GLP-1), 1 a product of the proglucagon gene, is released from gut endocrine cells and potentiates glucose-dependent insulin secretion (1). GLP-1 also regulates gastric emptying, food intake, glucagon secretion, and islet proliferation and hence is currently under investigation as a therapeutic agent for the treatment of diabetes (1). However, a significant limitation to potential GLP-1 therapy in diabetic subjects is the short biological half-life of this peptide (2-4), limiting its ability to control blood glucose for an extended period of time. These considerations have prompted investigation of strategies designed to prolong the duration of GLP-1 action in vivo (5, 6). Exendin-4, a peptide structurally related to but distinct from GLP-1 (7) was originally purified from the venom of a Heloderma suspectum lizard (8, 9). Subsequent characterization of exendin-4 activity demonstrated that the lizard peptide was a potent agonist for the mammalian glucagon-like peptide-1 receptor (GLP-1R) (8 -11). Exendin-4 exhibits a much longer in vivo half-life and prolonged duration of action (11), rendering it more potent for continuous stimulation of GLP-1 receptor signaling and sustained improvement in glucose homeostasis in vivo. Despite the structural homology of lizard exendin-4 and mammalian GLP-1, a ma...

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Synergy between amylin and cholecystokinin for inhibition of food intake in mice

Cited by 115 publications

References 26 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

Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys

Sustained Expression of Exendin-4 Does Not Perturb Glucose Homeostasis, β-Cell Mass, or Food Intake in Metallothionein-Preproexendin Transgenic Mice

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