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"LEPTIN’S ROLE IN HYPOTHALAMIC DEVELOPMENT AND OBESITY: MECHANISMS FOR IMPROVING LEPTIN SIGNALING"

by
Miranda D. Johnson
Integrative Neurosciences Program
B.S. 2009, Florida State University


Thesis Advisor: Barry E. Levin, M.D.
Professor
Department of Neurology

Thursday, July 2, 2015
11:15 A.M., Cancer Center, G-1196


Abstract

The adiposity hormone, leptin, is released in direct proportion to the amount of available body fat and acts on neurons in the hypothalamus to decrease food intake and increase energy expenditure in post-weaning rodents. Obese individuals have large amounts of circulating leptin, suggesting a resistance to the anorexigenic and thermogenic effects of the peptide. The selectively bred diet-induced obese rat (DIO) overeats and rapidly becomes obese when fed a 31% fat high-energy diet (HE), while the diet-resistant rat (DR) does not. Once they become obese, DIO rats avidly defend their elevated body weight. Subsequent studies have shown that this is the result of the DIO rat’s inherent leptin resistance. In addition to its effects on energy homeostasis, leptin is an important neurotrophic factor in postnatal hypothalamic development, promoting the growth of crucial leptin-dependent neuronal pathways that govern energy homeostasis in the adult.
In this dissertation, I examined postnatal leptin-sensitive hypothalamic neural developmental differences between DIO and DR rats with the overall goal of identifying potential targets to improve leptin sensitivity. The first set of experiments compared and identified the number of leptin sensitive proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons (many of which also express agouti-related peptide (AgRP)) across the rostral-caudal extent of the arcuate nucleus of the hypothalamus (ARC) at various ages during the first week of life. Using leptin-induced expression of STAT3 phosphorylation (pSTAT3) as a surrogate for leptin signaling, I found that DIO neonates have an inborn deficit in leptin signaling within the ARC NPY population at birth, while POMC neurons do not exhibit this deficit until the end of the first week of life.
The second set of experiments built upon these findings by utilizing an early intervention strategy to improve leptin signaling. Amylin is a pancreatic polypeptide hormone that is known to increase leptin signaling in the ventromedial hypothalamus (VMH) of adult rats. Outgrowth of axons from catabolic ARC POMC neurons expressing á-melanocyte stimulating hormone (áMSH) and anabolic NPY/AgRP neurons to the paraventricular nucleus (PVN) is dependent upon intact leptin signaling during the first 2 weeks of postnatal life in rats. Because of their inherent leptin resistance, these pathways are defective in DIO rats. Here, I administered amylin to DIO neonates during this time period and found that this increased their ARC leptin signaling and improved their leptin-dependent outgrowth from both sets of ARC neurons to their PVN targets. After cessation of amylin treatment, DIO rats continued to show increased ARC leptin signaling after five weeks on chow diet post-weaning, but neither ARC-PVN pathway nor leptin signaling enhancement were protective against increased body weight gain, food intake or adiposity when these DIO rats were placed on HE diet as adults. Finally, I demonstrated that amylin acts in the VMH to stimulate microglia to produce interleukin-6 (IL-6) which then acts synergistically with leptin to activate STAT3 and enhance leptin signaling in VMH neurons. I then showed that IL-6 knockout mice have decreased AgRP, but not áMSH ARC-PVN pathway development, compared to wild-type mice. Therefore, based on our results, I propose that amylin likely acts through two separate mechanisms to promote ARC-PVN outgrowth; amylin-induced IL-6 enhanced leptin signaling in AgRP neurons and direct amylin action on POMC neurons via phospho-ERK signaling.
In conclusion, our studies support a critical role for amylin during early hypothalamic development. We demonstrated that: 1) the DIO rat has inherent leptin resistance at birth in ARC NPY neurons and develop such resistance during the first week of postnatal life in ARC POMC neurons; 2) the DIO rat’s inherent reduction in leptin signaling and ARC-PVN pathway development can be improved by the use of early amylin administration; and 3) amylin likely acts as a leptin-sensitizer in AgRP neurons by an IL-6-dependent mechanism, whereas amylin may act directly on POMC neurons to increase áMSH projections through an IL-6/leptin-independent mechanism.


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