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The prevalence of obesity has increased alarmingly in the developed world over the last 20-30 years as cheap, highly palatable, fat-rich foods have become readily available. Since it is unlikely that our gene pool has significantly changed over this time, it is likely that environmental factors are the main culprit underlying the current obesity epidemic. As with obesity in most humans, the development of diet-induced obesity in rodents is inherited as a polygenic trait. Thus, the obesity-prone rat is an excellent experimental model, especially for the study of interactions between brain pathways that regulate energy intake, expenditure and storage, and hormones such as leptin, a signal from adipose tissue that informs the brain of the amount of fat in the body. We have used this model to determine the degree to which a raised threshold for sensing leptin’s negative feedback from increasing fat stores contributes to the obesity that develops in these animals when they are fed a high fat diet. We found that these rats, which we have selectively bred to be obesity-prone, do have such a raised threshold, also known as leptin resistance. This resistance is due to a reduced number of receptors for leptin on specialized nerve cells in the hypothalamus, which are key regulators of food intake and body weight. When we assessed these nerve cells individually in a dish, they exhibited exquisite sensitivity to leptin. Importantly, there were major differences between the leptin responsiveness of nerve cells from obesity-prone rats and those from obesity-resistant rats. These and other studies from our laboratory confirm that genetically inherited leptin resistance can be one predisposing factor in the development of obesity in animals fed high fat diets. Such studies provide insights into potential ways to treat or prevent human obesity.
Diet-induced obesity in rats shares several features with human obesity. These include reduced sensitivity to leptin, a key hormonal signal from fat tissue that informs the brain of increasing fat stores. Leptin circulates in the blood and enters the brain, where it exerts an inhibitory effect on food intake and an excitatory effect on energy expenditure when fat stores increase. We previously showed that rats selectively bred for their genetic propensity to become obese have an inborn elevation in their threshold for sensing and responding to the anorectic effects of leptin. This appears to be an important cause of their predisposition to become obese when fed a high fat diet.Over the last 3 years, I have carried out research in Dr. Barry Levin’s laboratory, comparing leptin signaling in rats selectively bred to be either obesity-prone or obesity-resistant. I first performed a detailed comparison of leptin binding in the brains of these rats (Figure 1) and found significant reductions in the arcuate (ARC), ventromedial (VMN) and dorsomedial (DMN) hypothalamic nuclei of obesity-prone rats. These nuclei play critical roles in the regulation of energy homeostasis, i.e. the balance between energy intake vs. energy expenditure and storage. Importantly, the reduced leptin binding was present before the obesity-prone rats were made obese on a high fat diet, suggesting that their reduced binding is genetically inherited and not due to dietary content or the development of obesity. Thus, the reduced responsiveness of obesity-prone rats to the negative feedback effects of leptin is likely to be due to a reduced number of receptors for this hormone on neurons in these key hypothalamic areas. For this reason, I carried out studies that used calcium imaging techniques in freshly dissociated neurons to demonstrate that individual ARC and VMN neurons respond to low levels of leptin in a concentration-dependent fashion. Importantly, I found that neurons from obesity-prone rats respond quite differently to leptin than do those from obesity-resistant rats suggesting that the leptin resistance of the former is present in individual hypothalamic neurons.
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Figure 1: Pseudocolor image of binding of 125I Leptin to its receptors in the arcuate (ARC), ventromedial (VMN) and dorsomedial (DMN) hypothalamic nuclei of a rat brain |
In summary, our data strongly support our previous findings, which show that a genetic predisposition to develop diet-induced obesity is associated with a raised threshold for detecting leptin signaling that is due to reduced numbers of leptin receptors on neurons in brain areas critical to the regulation of energy homeostasis. Such data suggest that drugs, which increase the number of these receptors, might be an effective way to prevent and treat the development of obesity. Lastly, we are optimistic that understanding the mechanisms by which the obese perinatal environment elicits permanent metabolic changes in offspring (e.g., altered leptin signaling) will provide a basis for future interventional studies in humans.
Boman Irani earned his PhD in 2005 from the Department of Medicinal Chemistry at the University of Florida under the supervision of Dr. Carrie Haskell-Luevano. He is currently carrying out his postdoctoral research under the guidance of Dr. Barry E. Levin in the Department of Neurology and Neurosciences, UMDNJ-New Jersey Medical School
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