The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 days) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4-11 wk) on food preference, energy expenditure, and body weight and composition. Furthermore, we describe the acute effect of amylin on locomotor activity and kaolin consumption to test for possible nonhomeostatic mechanisms that could affect food intake. Four-week subcutaneous amylin infusion of high-fat fed rats (3-300 microg.kg(-1).day(-1)) dose dependently reduced food intake and body weight gain (ED(50) for body weight gain = 16.5 microg.kg(-1).day(-1)). The effect of amylin on body weight gain was durable for up to 11 wks and was associated with a specific loss of fat mass and increased metabolic rate. The body weight of rats withdrawn from amylin (100 microg.kg(-1).day(-1)) after 4 wks of infusion returned to control levels 2 wks after treatment cessation, but did not rebound above control levels. When self-selecting calories from a low- or high-fat diet during 11 wks of infusion, amylin-treated rats (300 microg.kg(-1).day(-1)) consistently chose a larger percentage of calories from the low-fat diet vs. controls. Amylin acutely had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. These results demonstrate pharmacological actions of amylin in long-term body weight regulation in part through appetitive-related mechanisms and possibly via changes in food preference and energy expenditure.

Objective: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. Research design and methods: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. Results: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). Conclusion: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. Methods and results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 mg/kg/ day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 mg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 mg/kg/day (Po0.05). Decreased body weight gain was associated with a significant decrease in fat mass (Po0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (Po0.05). Exenatide at 10 mg/kg significantly reduced food intake (Po0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

In rodents, weight reduction after peptide YY[3-36] (PYY[3-36]) administration may be due largely to decreased food consumption. Effects on other processes affecting energy balance (energy expenditure, fuel partitioning, gut nutrient uptake) remain poorly understood. We examined whether s.c. infusion of 1 mg/(kg x d) PYY[3-36] (for up to 7 d) increased metabolic rate, fat combustion, and/or fecal energy loss in obese mice fed a high-fat diet. PYY[3-36] transiently reduced food intake (e.g., 25-43% lower at d 2 relative to pretreatment baseline) and decreased body weight (e.g., 9-10% reduction at d 2 vs. baseline) in 3 separate studies. Mass-specific metabolic rate in kJ/(kg x h) in PYY[3-36]-treated mice did not differ from controls. The dark cycle respiratory quotient (RQ) was transiently decreased. On d 2, it was 0.747 +/- 0.008 compared with 0.786 +/- 0.004 for controls (P < 0.001); light cycle RQ was reduced throughout the study in PYY[3-36]-treated mice (0.730 +/- 0.006) compared with controls (0.750 +/- 0.009; P < 0.001). Epididymal fat pad weight in PYY[3-36]-treated mice was approximately 50% lower than in controls (P < 0.01). Fat pad lipolysis ex vivo was not stimulated by PYY[3-36]. PYY[3-36] decreased basal gallbladder emptying in nonobese mice. Fecal energy loss was negligible ( approximately 2% of ingested energy) and did not differ between PYY[3-36]-treated mice and controls. Thus, negative energy balance after PYY[3-36] administration in diet-induced obese mice results from reduced food intake with a relative maintenance of mass-specific energy expenditure. Fat loss and reduced RQ highlight the potential for PYY[3-36] to drive increased mobilization of fat stores to help meet energy requirements in this model.

In rodents, ovariectomy (OVX) elicits weight gain and diminished responsiveness to homeostatic signals. Here we characterized the response of obese OVX rats to peripheral amylin. Rats received sham surgery (SHAM), OVX, or OVX with hormonal replacement (17β-estradiol, 2 μg per 4 d; OVX+E) and were infused with vehicle or amylin (50 μg/kg · d) for 28 d. Amylin reduced body weight (5.1 ± 1.1%) and food intake (10.9 ± 3.4%) in SHAM rats but was twice as efficacious in OVX rats in reducing weight (11.2 ± 1.9%) and food intake (23.0 ± 2.0%). There were no differences between amylin-treated SHAM and OVX+E rats. OVX decreased metabolic rate (∼24%) and increased respiratory exchange ratio relative to SHAM. Amylin partially normalized metabolic rate (13% increase) in OVX rats and decreased respiratory exchange ratio in OVX and SHAM rats. Regarding central mechanisms, amylin infusion corrected the OVX-induced decrease in hippocampal neurogenesis and increased immobility in the forced swim test. Additionally, amylin increased neurogenesis (∼2-fold) within the area postrema of OVX rats. To assess the contribution of endogenous leptin to amylin-mediated weight loss in OVX rats, amylin was administered to SHAM or OVX Zucker diabetic fatty rats. In SHAM rats, amylin infusion reduced food intake but not body weight, whereas in OVX Zucker diabetic fatty rats, food intake, body weight, and insulin were reduced. Overall, amylin induced greater body weight loss in the absence of estradiol via central and peripheral actions that did not require leptin. These findings support the clinical investigation of amylin in low estradiol (e.g. postmenopausal) states.