Elsevier

Physiology & Behavior

Volume 104, Issue 1, 25 July 2011, Pages 20-28
Physiology & Behavior

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

https://doi.org/10.1016/j.physbeh.2011.04.044Get rights and content

Abstract

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 μg/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 μg/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 μg/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 μg/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.

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)

  • M. Olsson et al.

    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

    (2007)
  • P.Y. Wielinga et al.

    Central amylin acts as an adiposity signal to control body weight and energy expenditure

    Physiol Behav

    (2010)
  • S. Gebre-Medhin et al.

    Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin)

    Biochem Biophys Res Commun

    (1998)
  • M. Maffei et al.

    Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects

    Nat Med

    (1995)
  • J.D. Bagdade et al.

    The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects

    J Clin Invest

    (1967)
  • B.E. Levin et al.

    Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset

    Am J Physiol Regul Integr Comp Physiol

    (2004)
  • D.J. Clegg et al.

    Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet

    Am J Physiol Regul Integr Comp Physiol

    (2005)
  • W.A. Banks

    Blood-brain barrier as a regulatory interface

    Forum Nutr

    (2010)
  • H. Munzberg

    Leptin-signaling pathways and leptin resistance

    Forum Nutr

    (2010)
  • Z.A. Knight et al.

    Hyperleptinemia is required for the development of leptin resistance

    PLoS One

    (2010)
  • S.D. Primeaux et al.

    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)

    (2010)
  • T.R. Pieber et al.

    Direct plasma radioimmunoassay for rat amylin-(1–37): concentrations with acquired and genetic obesity

    Am J Physiol

    (1994)
  • A. Leckstrom et al.

    Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (ob/ob) mouse

    Pancreas

    (1999)
  • Cited by (42)

    • Creating the amylin story

      2022, Appetite
      Citation Excerpt :

      Amylin is co-packaged with insulin into the same secretory vesicles, and the same physiological stimuli lead to their co-release. Hence, circulating plasma amylin which ranges from 3 to 5 pM in the fasting state, increases post-prandially to concentrations of approx. 15–25 pM in rats (Boyle, Rossier, & Lutz, 2010, 2011). Further, the incretin glucagon-like peptide-1 (GLP-1) not only increases insulin but also amylin levels (Inoue, Hisatomi, Umeda, & Nawata, 1991).

    • Amylin and Leptin interaction: Role During Pregnancy, Lactation and Neonatal Development

      2020, Neuroscience
      Citation Excerpt :

      We, in fact, previously observed this phenomenon, when rats restricted to 80% of ad libitum food intake were non-responsive to amylin’s satiating effect (Boyle et al., 2011). Together these observations suggest that amylin’s action to induce satiation or potentiate leptin signaling is least effective in instances of absent or low leptin signaling, such as genetic leptin- or Lepr-deficiency, extreme obesity, or following chronic food restriction (Boyle and Lutz, 2011; Boyle et al., 2011; Eiden et al., 2002; Trevaskis et al., 2016). Pregnancy and lactation are two metabolically dynamic periods of a female’s life when both the levels of and receptivity to sex and metabolic hormones are changing rapidly.

    • Circadian Changes in Gut Peptide Levels and Obesity

      2020, Neurological Modulation of Sleep: Mechanisms and Function of Sleep Health
    • The BDNF Protein and its Cognate mRNAs in the Rat Spinal Cord during Amylin-induced Reversal of Morphine Tolerance

      2019, Neuroscience
      Citation Excerpt :

      The pancreatic hormone, Islet amyloid polypeptide or Amylin (AMY), works with insulin in glucose regulation (Young, 2005) and energy balance (Boyle et al., 2011).

    View all citing articles on Scopus
    View full text