Individual differences in body weight regulation are partially determined by genetic factors [1
]. Nevertheless, a detailed account of the hereditary effects on adiposity has been elusive to date, in part because a large number of genes that may each play a minor role [6
]. Furthermore, genetic influences are likely to interact with environmental effects, such as diet and lifestyle. Given the increasing incidence, earlier onset, and negative health consequences of obesity [7
], there is great interest in discovering the neurological mechanisms through which genes can affect obesity.
A useful animal model for human obesity is the selective breeding of outbred Sprague-Dawley rats [12
]. One strain has been selectively inbred to resist weight gain when placed on a 31% fat, high-energy (HE) diet, referred to as diet-resistant (DR) rats. In contrast, another strain has been inbred to select for offspring that increase body weight on this diet, referred to as diet-induced obesity (DIO) rats. Several physiological variables are correlated with these body weight phenotypes. These include decreased anorectic and thermogenic responses to the adipocyte hormone leptin [13
], in association with reduced leptin receptor mRNA, leptin binding, and leptin signaling in the hypothalamus in the DIO rats compared with the DR rats [14
]. These obesity-strain differences were primarily localized to the hypothalamic ventromedial nucleus (VMH).
Discrete regions within the medulla, hypothalamus and limbic system are known to play a role in the control of food intake and body weight. Many studies have highlighted the roles of the arcuate nucleus, paraventricular nucleus, and lateral hypothalamic area. Several lines of evidence support the inclusion of the VMH in this distributed neural network. For example, animals with a disruption of the SF-1 gene, which manifests with a very selective deficit in VMH neuronal development, have marked dysregulation of energy balance [16
]. SF-1 expression in the VMH is linked to leptin receptor-containing neurons in the VMH. These receptors are critical for normal energy balance, such that deletion of the leptin receptor from SF-1 neurons produces mice that become obese on a high fat diet [17
]. Importantly, the VMH is one of the sites where DIO rats display deficient leptin receptors and leptin signaling. In fact, the expression of these receptors is selectively altered in the VMH by cross-fostering DR offspring to obese DIO dams or, conversely, cross-fostering DIO offspring with DR mothers [18
]. Other energy balance-related genes expressed in the VMH include the ATP-sensitive potassium channel, glucose transporters, and glucokinase [19
]. In addition, our laboratory recently has demonstrated that food deprivation is associated with structural plasticity of VMH dendrites [22
]. It is unknown whether or not an inherited basis for altered food intake also might be associated with changes in VMH dendrites.
Acute and developmental effects of metabolic status have been shown to alter synaptic activity and hypothalamic connectivity [23
]. Given that DIO rats have abnormal hypothalamic connections and reduced areal extent of the VMH [26
], we postulated that DIO rats would exhibit specific remodeling within the dendritic arbor of VMH neurons. To test this hypothesis, the dendritic arbor of Golgi-impregnated VMH neurons was assessed in DR and DIO rats maintained on either rat chow or HE diet.