Severity of dietary-obesity in wistar rats: relationship with melanocortin system activity L. Tarry, J. Harrold, R. Cassidy, C. Sadler, J.Wilding and G.Williams. Dept. Medicine, Liverpool University, L69 3GA.	Print Abstract Search PubMed for: Tarry L Harrold J Cassidy R Sadler C Wilding J Williams G

Voluntary overeating of palatable food and the dietary obesity that results is the closest rodent model to 'common' obesity in humans. As in humans, only a susceptible group of rats presented with a palatable diet will become significantly obese (Harrold et al., 2000). This appears to depend critically on the nature of the diet used. This study examines the influences of diets differing in composition and palatability on weight gain in a single rat strain and focuses on the contribution of the melanocortin (MC) system - a major brain pathway known to participate in the control of energy balance - in determining susceptibility to the development of obesity. Quantitative receptor autoradiography with 50 pM [¹²⁵I] [Nle⁴ D-Phe⁷]--MSH (and 3 µM -MSH to define non-specific binding) was used to measure the density of MC receptors (both MC3-R and MC4-R) in key appetite-regulating regions. 100 nM ²-MSH was employed to mask MC3-R from MC4-R (Harrold et al., 1999). Twenty eight male Wistar rats (150 g) were divided into 4 groups (each n=7) and fed [1] palatable diet [2] biscuit diet [3] high (40%) fat diet or [4] normal rodent chow for 10 weeks. Following this feeding period, weight gain of the palatable and biscuit diet-fed groups was significantly greater than that of chow-fed controls (e.g. 538±15 [biscuit] vs 471±29 g; p<0.05 Students t-test). However, weight gain of the high-fat diet group did not exceed that of control animals. Consistent with previous studies (Harrold et al., 1999), specific [¹²⁵I]NDP-MSH binding in chow-fed controls was highest in the hypothalamic ventromedial, dorsomedial (DMH) and arcuate (ARC) nuclei and median eminence and the extrahypothalamic median habenular nucleus. The palatable diet fed group showed selective decreases in MC-R binding in all hypothalamic areas (e.g. ARC 0.17±0.004 vs 0.28±0.03 fmol/mg tissue; p<0.01). However the ²-MSH sensitive component (MC3-R) was not significantly different from chow-fed controls, demonstrating that down-regulation of receptor density is attributable entirely to MC4-R. This also confirms previous results and is consistent with increased MC4-R activity and thus enhanced satiety signalling (Harrold et al., 1999). A comparable degree of MC4-R down-regulation was also observed in the biscuit and high-fat diet-fed groups, despite the body weight of the latter being similar to controls. It has previously been shown that early leptin responses, preceding significant weight gain, have long-term effects in determining feeding behaviour and weight gain in individual Wistar rats by influencing MC4-R activity (Harrold et al., 2000). Plasma leptin levels at 4 weeks (as measured by radioimmunoassay) showed a strikingly significant increase in all diet-fed groups compared to controls and a significant negative correlation with MC4-R density in the DMH and ARC. However, our findings suggest that MC4-R activity is not a determinant of the degree of weight gain in the diet-fed groups. Other factors must influence the drive to eat and determine body weight. Factors concerned with palatability or related to the sweetness and sugar content of the biscuit and palatable diets may activate reward systems within the CNS, which are concerned with hedonic aspects of eating. Further work may identify them as determinants of dietary obesity.

[1] Harrold J, et al., (1999) Diabetes 48, 267-271.
[2] Harrold J, et al., (2000) J. Neurochem. 74, 1224-1228.