Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin
Research highlights
► Long-term maintenance on a HF diet only slightly attenuates acute amylin action. ► Attenuation of amylin action seems more related to obesity than HF exposure. ► Acute amylin sensitivity is not reduced by chronic hyperamylinemia.
Introduction
Obesity typically results in increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin [1], [2]; elevated circulating levels of these adiposity signals in obesity eventually results in the decreased peripheral and central sensitivity to leptin and insulin [3], [4], respectively, which only further potentiates the obese state. Leptin-resistance, for example, is present in diet-induced obese (DIO) mice and rats, and is thought to result from several factors including defective leptin receptor signaling and decreased leptin transport across the blood brain barrier [Reviewed in [5], [6]]. It was also shown recently that hyperleptinemia is required for the full development of leptin resistance [7]. Obesity can also affect the sensitivity to satiation hormones, which control meal size, such as glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) [8], [9].
Increased circulating levels of amylin have also been described in obese humans and rodents (“tonic” increase) [10], [11], [12]. Amylin is a pancreatic hormone which buffers glucose flux during a meal by decreasing food intake, gastric emptying, and glucagon secretion. Thus, in response to nutrient ingestion, circulating amylin concentrations rise rapidly within minutes after meal onset (“phasic” increase), peak within 60 min, and return to baseline by 120 min [13]. When administered exogenously (peripherally or centrally), acute amylin dose-dependently decreases food intake, causing a decrease in meal size though having no effect on the intermeal interval [14], [15]. Furthermore, the decrease in meal size is not a result of an aversive or toxic effect of amylin [14], [16].
Some rodent models of obesity (e.g. ob/ob and MC4Rko mice, fa/fa rats) require higher doses of the amylin receptor agonist, salmon calcitonin (sCT) to reduce eating [17], suggesting that obesity may attenuate amylin sensitivity. Previous pilot work has also indicated that high circulating amylin levels may reduce the ability of amylin to slow gastric emptying [18]. Furthermore, clinical tests report that higher doses of the amylin analog, pramlintide, are necessary to promote weight loss in type 2 versus type 1 diabetics, suggesting that amylin deficiency, as found in type 1 diabetics, may perhaps increase the efficacy of exogenous amylin [19].
Based on these data, we tested whether amylin sensitivity is inversely correlated with adiposity, such that diet-induced obesity reduces the anorectic action of acute amylin. We also determined if factors that cause obesity, such as consumption of a high-fat diet, or that are associated with obesity, such as hyperamylinemia, can lead to a change in amylin sensitivity, independently of obesity.
Section snippets
Experimental animals
Sprague-Dawley rats (initial body weight 240-300 g; Harlan NM Horst, the Netherlands) were used for all experiments; some animals served as a model for diet-induced obesity (DIO). The animals were individually housed in hanging, stainless steel wire-mesh cages and were maintained in a temperature-controlled environment (21 ± 2 °C), on a 12/12 h light-dark cycle. Water and food were accessible ad libitum, unless otherwise indicated. All rats were habituated to the housing conditions for at least one
Development of DIO
Baseline body weight was similar across groups (240-260 g), with no significant differences at the start of the experiment. Fig. 1A shows the average body weight of the three groups for the duration of the study. At the beginning of week 12 (day 77), the restricted rats were switched to the HF diet, which was then offered ad libitum for the remainder of the experiment.
Comparison of the average body weights of the chow control group and the HF fed animals, demonstrates a demarcation between obese
Discussion
The aims of this study were to investigate the influence of body weight, exposure to a HF diet, and hyperamylinemia on the sensitivity to acute amylin injections in rats. The results of our studies suggest three main points. First, the suppression of food intake by a variety of amylin doses was comparable between rats fed chow or HF diet for up to 10 weeks. Second, maintenance on a HF diet for longer duration and resulting obesity, only slightly attenuated the anorectic response to acute amylin.
Acknowledgement
We gratefully acknowledge the financial support by the Swiss National Science Foundation, the Vontobel Foundation and the Novartis Foundation.
References (46)
- et al.
Rats maintained on high-fat diets exhibit reduced satiety in response to CCK and bombesin
Peptides
(1998) - et al.
Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus
Diabetes Res Clin Pract
(1992) - et al.
Amylin concentrations and glucose control
Lancet
(1992) - et al.
Amylin decreases meal size in rats
Physiol Behav
(1995) Inhibition of gastric emptying
Adv Pharmacol
(2005)- et al.
Effect of meal pattern during food restriction on body weight loss and recovery after refeeding
Physiol Behav
(1993) - et al.
Caloric restriction and refeeding promoted different metabolic effects in fat depots and impaired dyslipidemic profile in rats
Nutrition
(2008) - et al.
Consumption of a high-fat diet induces central insulin resistance independent of adiposity
Physiol Behav
(2011) - et al.
Ghrelin infused into the portal vein inhibits glucose-stimulated insulin secretion in Wistar rats
Peptides
(2008) - et al.
Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats
Peptides
(1998)
Comparison of the effects of chronic central administration and chronic peripheral administration of islet amyloid polypeptide on food intake and meal pattern in the rat
Peptides
Central amylin acts as an adiposity signal to control body weight and energy expenditure
Physiol Behav
Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin)
Biochem Biophys Res Commun
Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects
Nat Med
The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects
J Clin Invest
Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset
Am J Physiol Regul Integr Comp Physiol
Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet
Am J Physiol Regul Integr Comp Physiol
Blood-brain barrier as a regulatory interface
Forum Nutr
Leptin-signaling pathways and leptin resistance
Forum Nutr
Hyperleptinemia is required for the development of leptin resistance
PLoS One
Sensitivity to the satiating effects of exendin 4 is decreased in obesity-prone Osborne-Mendel rats compared to obesity-resistant S5B/Pl rats
Int J Obes (Lond)
Direct plasma radioimmunoassay for rat amylin-(1–37): concentrations with acquired and genetic obesity
Am J Physiol
Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (ob/ob) mouse
Pancreas
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