Oregon Health & Science University
While the prevalence of obesity is increasing, the treatment of obesity has been disappointing for researchers, because the mechanisms that regulate body weight homeostasis and adiposity are incompletely understood. Food intake is tightly regulated by external factors such as food availability and palatability, as well as by internal factors including the hormonal status related to energy homeostasis. These circulating factors communicate with a complex network of feeding neurocircuitry to maintain body weight homeostasis. Interactions between circulating hormones and the neurons in the arcuate nucleus of the hypothalamus (ARH) have been extensively characterized. Neuropeptide Y (NPY) neurons in the ARH are particularly important because they stimulate food intake and promote positive energy balance. In specific physiological conditions such as lactation and obesity, NPY neurons in the dorsomedial hypothalamus (DMH) appear to play a critical role in feeding behavior and energy expenditure. However, DMH-NPY neurons have not received much attention until recent years. Emerging evidence suggests that DMH-NPY neurons are highly implicated in the development of obesity by promoting energy intake over energy expenditure. The exact mechanisms by which DMH-NPY neurons regulate these behaviors are still poorly understood. The goal of this thesis is to expand the neuroanatomical knowledge of DMH-NPY neurons that are activated during specific conditions, including development, lactation and obesity, to better understand the mechanisms of these neurons in feeding behavior. Chapter 1 provides a review of the current knowledge of hypothalamic regulation of body weight homeostasis with particular emphasis on the anatomy and functions of the DMH neurons. Chapter 2 describes the results of microarray gene analysis presenting alternate phenotypes of DMH-NPY neurons isolated from developing mice. Chapter 3 illustrates biotinylated dextran amine (BDA)-labeled DMH-NPY neuronal projections in the lactation and diet-induced obese (DIO) mouse model with a particular focus on hypothalamic projections in the areas highly implicated in the regulation of feeding behavior and energy expenditure. Chapter 4 focuses on the characterization of DMH-NPY induction in the diet induced obesity (DIO) mouse model. A surprising finding from this study is that leptin may regulate DMH-NPY neuronal activity in obesity. CART co-expression in DMH-NPY neurons also raises several questions regarding the role of leptin and CART in DIO conditions. Finally, chapter 5 integrates findings from three different DMH-NPY induction models and discusses different mechanisms leading to the activation of DMH-NPY neurons which results in hyperphagic behavior. In summary, these findings contribute to the understanding of neural adaptations occurring during specific physiological states that favor excess energy intake and some of the neural pathways that may account for hyperphagia.
Neuroscience Graduate Program
School of Medicine
Lee, Shin Jae, "Implications of neuropeptide Y induction in the dorsomedial hypothalamus for hyperphagia and obesity" (2011). Scholar Archive. 716.