Thesis (M.S.)--University of Wisconsin--Madison, 1982. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 63-73).

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

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The study of the role of adipose tissue in the maintenance of the caloric homeostasis of organisms is currently the object of widespread research. In particular, the enzymes of lipid metabolism in adipose tissue are being extensively investigated in both intact fat pads and in broken-cell preparations. Special attention is being paid to factors which control the activity of these enzymes. We have examined some properties of a lipase in epididymal fat pads of rats. The enzyme has been assayed by measuring the free fatty acids liberated when triglycerides are incubated with crude adipose tissue extracts. Quantitative measurements of free fatty acids were performed by (a) titrating the liberated acid with dilute alkali solution, and (b) reacting the free fatty acids with Cu⁺⁺ to form the chloroform-soluble copper soap of long chain fatty acids, then assaying the copper with diethyl-dithiocarbamate spectrophotometrically. It is well known that lipase activity in adipose tissue decreases during incubation in a Krebs-Ringer bicarbonate medium at 37°C. The de-activated enzyme can be activated by briefly exposing the intact tissue to epinephrine. The study of this epinephrine-sensitive lipase in adipose tissue has been the main object of this thesis. When epinephrine was added to media containing intact epididymal fat pads, the dramatic mobilization of free fatty acids from the pads into the media was observed. When epinephrine was added directly to unfractionated homogenates, little, if any, response was elicited, indicating perhaps that some activating factor was destroyed or diluted out during homogenization. When ATP, cyclic 3',5'-AMP and Mg⁺⁺ were added to unfractionated homogenates of adipose tissue, some lipase activation was observed. Similarly, when these nucleotides and Mg⁺⁺ were added to the supernatant fluid obtained from centrifuged homogenates, some activation of the lipase was observed, although the results obtained were not consistent. Other nucleotide 3',5'-cyclic phosphates generally inhibited lipase activity in the supernatant fluid. Our data indicates that epinephrine activates adipose tissue lipase only when added to the intact fat pad before homogenization. Little or no activation occurred when the amine was added to homogenates. Cyclic 3',5'-AMP had some ability to reactivate the lipase, both in unfractionated homogenates and in the supernatant fluid prepared by centrifugation. The effects, however, were not marked. It is concluded that if epinephrine-activation of adipose tissue is mediated through cyclic 3',5'-AMP, precise conditions for showing this have not yet been achieved. Additional experiments were performed on the epinephrine-sensitive lipase. Intact adipose tissue obtained from reserpinized rats was exposed to epinephrine after a 3-hour incubation period. The results indicated that epinephrine does not activate the lipolytic system in adipose tissue of reserpinized rats. Finally, some of the factors regulating the degree of inactivation of the epinephrine-sensitive lipase during incubation were investigated. Fat pads removed from rats which had been either anaesthetized or not anaesthetized prior to sacrifice were incubated for 3 hours. Data collected from a number of experiments indicated that there were virtually no differences in the extent of lipase inactivation between the two groups of rats. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

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Ellen Lai Ping Chan. / Thesis (Ph.D)--Chinese University of Hong Kong, 1990. / Bibliography: leaves 238-272. / Chapter CHAPTER I --- LITERATURE REVIEW / Chapter 1. --- History --- p.1 / Chapter 2. --- Species Distribution of BAT --- p.3 / Chapter 3. --- Distribution of BAT --- p.4 / Chapter 4. --- Structure of BAT --- p.4 / Chapter 4.1. --- Macroscopic Appearance --- p.4 / Chapter 4.1.1. --- Innervation --- p.4 / Chapter 4.1.2. --- Blood supply --- p.5 / Chapter 4.2. --- Microscopic Structure of BAT --- p.6 / Chapter 4.3. --- Difference Between Brown Fat and White Fat --- p.9 / Chapter 5. --- Composition of BAT --- p.11 / Chapter 6. --- The Mechanisms of Brown Adipose Tissue Thermogenesis --- p.12 / Chapter 6.1. --- Factors Influencing Proton Transport by UCP --- p.16 / Chapter 6.2. --- Postulated Sequence of Events during Thermogenesis --- p.18 / Chapter 7. --- Measurements of thermogenic Capacity of BAT --- p.21 / Chapter 8. --- Age-related Differences in BAT --- p.28 / Chapter 9. --- Non-shivering Thermogenesis and BAT --- p.32 / Chapter 9.1. --- Changes In BAT During Cold Acclimation --- p.35 / Chapter 9.1.1. --- GDP Binding --- p.35 / Chapter 9.1.2. --- Concentration of UCP --- p.37 / Chapter 9.1.3. --- Metabolic changes in BAT during Cold Acclimation --- p.39 / Chapter 10. --- Diet-induced Thermogenesis and BAT --- p.41 / Chapter 10.1. --- Mechanism of DIT --- p.42 / Chapter 10.2. --- Controversies in DIT --- p.44 / Chapter 10.3. --- Nutritional Factors Inducing DIT --- p.46 / Chapter 10.4. --- DIT in Man --- p.47 / Chapter 10.5. --- Neuroendocrine Control of BAT in DIT --- p.48 / Chapter 10.6. --- Effects of Fasting in BAT --- p.51 / Chapter 11. --- Obesity and BAT --- p.53 / Chapter 11.1. --- NST and DIT in Obese Animals --- p.58 / Chapter 11.2. --- Regulation of BAT in Obese Animals --- p.59 / Chapter 11.2.1. --- Sympathetic Nervous System in Obese Animals --- p.59 / Chapter 11.2.2. --- Corticosteriods in Obese Animals --- p.61 / Chapter 11.2.3. --- Adrenergic Receptors in Obese Animals --- p.63 / Chapter 11.2.4. --- Insulin in Obese Animals --- p.64 / Chapter 12. --- Pregnancy and Lactation and BAT --- p.67 / Chapter 12.1. --- Energy Balance During Pregnancy and Lactation --- p.67 / Chapter 12.2. --- Some Metabolic Changes During X Pregnancy and Lactation --- p.68 / Chapter 12.3. --- Role of BAT in Pregnancy and Lactation --- p.70 / Chapter 12.4. --- Mechanism of Regulation of Thermogenesis during Pregnancy and Lactation --- p.71 / Chapter 13. --- Factors Controlling the Thermogenesis --- p.75 / Chapter 13.1. --- Sympathetic Nervous Control --- p.75 / Chapter 13.1.1. --- Studies of Administration of Noradrenaline --- p.75 / Chapter 13.1.2. --- Control of the Fuel Supply to BAT by Sympathetic Nervous System --- p.77 / Chapter 13.1.3. --- Sympathetic denervation --- p.78 / Chapter 13.2. --- Hormonal Control --- p.79 / Chapter 13.2.1. --- Thyroid Hormone --- p.79 / Chapter 13.2.2. --- Insulin --- p.81 / Chapter 13.2.3. --- Pituitary Hormones --- p.83 / Chapter 13.2.4. --- Glucocorticoids --- p.83 / Chapter 13.2.5. --- Corticotropin-Releasing Factor --- p.85 / Chapter 14. --- Aims of the Study --- p.87 / Chapter CHAPTER II --- ISOLATION AND PURIFICATION OF UCP AND DEVELOPMENT OF AN ENZYME LINKED IMMUNOSORBENT ASSAY FOR UCP / Chapter 1. --- INTRODUCTION --- p.88 / Chapter 2. --- MATERIALS AND METHODS --- p.89 / Chapter 2.1. --- Animals --- p.89 / Chapter 2.2. --- Collection of BAT --- p.89 / Chapter 2.3. --- Isolation of Mitochondria --- p.90 / Chapter 2.4. --- Electron Microscopy (EM) of Isolated BAT Mitochondria --- p.92 / Chapter 2.5. --- Measurement of Protein and Cytochrome C Oxidase Activity --- p.94 / Chapter 2.5.1. --- Measurement of Protein Concentration --- p.94 / Chapter 2.5.2. --- Measurement of Cytochrome C Oxidase Activity --- p.99 / Chapter 2.6. --- GDP Binding Assay of BAT Mitochondria --- p.101 / Chapter 2.6.1. --- GDP Binding Assay of Mitochondria by Centrifugation Method --- p.103 / Chapter 2.6.2. --- GDP: Binding Activity by Equilibrium Dialysis --- p.106 / Chapter 2.6.3. --- GDP Binding by Microfiltration Method --- p.108 / Chapter 2.7. --- Experiments Designed for Validation of GDP Binding Assay --- p.109 / Chapter 2.7.1. --- GDP Binding Activity in BAT Mitochondria after Noradrenaline Treatment --- p.109 / Chapter 2.7.2. --- GDP Binding Activity in BAT Mitochondria after Cold Acclimation and Noradrenaline Treatment --- p.110 / Chapter 2.7.3. --- Effect of Food Restriction on Cold Acclimated Rats --- p.110 / Chapter 2.7.4. --- GDP Binding Activity of BAT Mitochondria of Rats of Different Ages --- p.111 / Chapter 2.8. --- Isolation and Purification of UCP --- p.111 / Chapter 2.9. --- Sodium Dodecyl Sulphate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) --- p.115 / Chapter 2.10. --- Methods for Raising Anti-Rat-UCP Antibody and the Characterization of Antiserum --- p.120 / Chapter 2.10.1. --- Raising Rabbit Anti-Rat-UCP Antibody --- p.120 / Chapter 2.10.2. --- Western Blot Analysis For Cross Reactivity Study --- p.120 / Chapter 2.10.3. --- Immuno-Autoradiographic Method for Detection of Specificity of Rabbit Anti-Rat UCP Antiserum --- p.121 / Chapter 2.11. --- Enzyme Linked Immunosorbent Assay For UCP --- p.124 / Chapter 2.12. --- Experiment Designed to Validate the ELISA --- p.129 / Chapter 2.13. --- Statistical Analysis --- p.129 / Chapter 3. --- RESULTS --- p.130 / Chapter 3.1. --- Electron Microscopy of Isolated BAT Mitochondria --- p.130 / Chapter 3.2. --- GDP Binding Assay of BAT Mitochondria --- p.130 / Chapter 3.3. --- Experiments Designed for Validation of GDP Binding Assay --- p.133 / Chapter 3.3.1. --- GDP Binding Activity of BAT Mitochondria after Noradrenaline Injection --- p.133 / Chapter 3.3.2. --- GDP Binding Activity of BAT Mitochondria after Cold Acclimation and Noradrenaline Treatment --- p.136 / Chapter 3.3.3. --- Effects of Food Restriction on Cold Acclimated Rats --- p.136 / Chapter 3.3.4. --- GDP Binding Activity of BAT Mitochondria from Rats of Different Ages --- p.140 / Chapter 3.4. --- Isolation and Purification of UCP --- p.140 / Chapter 3.4.1. --- Results of SDS-PAGE --- p.143 / Chapter 3.4.2. --- Results of GDP Binding Activity --- p.149 / Chapter 3.5. --- Rabbit Anti-rat-UCP Antibody and the Characterization of Antiserum --- p.151 / Chapter 3.5.1. --- Immuno-autoradiography for Specificity of Rabbit Anti-rat-UCP Antiserum --- p.153 / Chapter 3.5.1.1. --- Cross-reactivity of the Rabbit Anti-rat-UCP Antiserum to Mitochondrial Proteins of BAT and from other Tissues --- p.153 / Chapter 3.5.1.2. --- Cross-reactivity of the Rabbit Anti-rat-UCP Antiserum to BAT Mitochondrial Protein from Different Rodent Species --- p.156 / Chapter 3.5.1.3. --- Dose Response of Rabbit Anti-rat-UCP Antiserum to UCP --- p.159 / Chapter 3.6. --- ELISA of UCP --- p.161 / Chapter 3.6.1. --- Determination of Maximum Amount of UCP Binding on Microtitre Plate --- p.161 / Chapter 3.6.2. --- Antibody Dilution Curve --- p.161 / Chapter 3.6.3. --- Incubation Time for Enzyme-Substrate Reaction --- p.163 / Chapter 3.6.4. --- Competitive ELISA --- p.163 / Chapter 3.6.5. --- Precision of ELISA --- p.167 / Chapter 3.7. --- Experiment Designed for Validation of ELISA by Measuring UCP in Cold Acclimated Rats --- p.170 / Chapter 4. --- DISCUSSION --- p.172 / Chapter 4.1. --- GDP Binding Assay of BAT Mitochondria --- p.172 / Chapter 4.2. --- Isolation and Purification of UCP --- p.176 / Chapter 4.3. --- Development and Evaluation of ELISA --- p.178 / Chapter CHAPTER III --- CHANGES IN BAT DURING PREGNANCY AND LACTATION AND ROLE OF PROLACTIN / Chapter 1. --- INTRODUCTION --- p.184 / Chapter 2. --- MATERIALS AND METHODS --- p.187 / Chapter 2.1. --- Animal --- p.187 / Chapter 2.2. --- Experimental Designs --- p.187 / Chapter 2.2.1. --- "Effects of Pregnancy, Lactation and Post Weaning on BAT" --- p.187 / Chapter 2.2.2. --- Effect of Metoclopramide on BAT --- p.188 / Chapter 2.2.3. --- Effect of Metoclopramide and Bromocriptine on BAT --- p.188 / Chapter 2.2.4. --- Effect of PRL Injection on BAT --- p.189 / Chapter 2.2.5. --- Continuous infusion of PRL --- p.189 / Chapter 2.6.6. --- Measurements of BAT Parameters --- p.191 / Chapter 2.2.7. --- RIA of serrum PRL --- p.191 / Chapter 2.2.8. --- PRL Receptors in BAT --- p.197 / Chapter 2.4. --- Statistical Analysis --- p.201 / Chapter 3. --- RESULTS --- p.202 / Chapter 3.1. --- Effects of Pregnancy and Lactation --- p.202 / Chapter 3.1.1. --- Food Consumption and Body Weight --- p.202 / Chapter 3.1.2. --- BAT --- p.205 / Chapter 3.1.3. --- Serum PRL level --- p.209 / Chapter 3.2. --- Effects of PRL njection --- p.213 / Chapter 3.3. --- Effects of Continuous Infusion of PRL on BAT --- p.213 / Chapter 3.4. --- Effects of Metoclopramide on BAT --- p.216 / Chapter 3.5. --- Effects of Bromocriptine and Metoclopramide on BAT --- p.216 / Chapter 3.6. --- PRL Receptor in BAT --- p.219 / Chapter 4. --- DISCUSSION --- p.223 / GENERAL CONCLUSION --- p.236

Brown and beige fat are specialized adipose tissues found in almost all mammals that can increase energy expenditure and produce heat. Cold exposure and b3-adrenergic stimulation has been extensively shown to activate brown adipose tissue (BAT) in rodents, which promotes uncoupled respiration of glucose and lipid substrates via uncoupling protein 1 (UCP1). Prolonged stimulation can induce white adipose browning, which leads to the emergence of thermogenic cells within white fat depots, called beige adipocytes. The beige adipocyte possesses a unique molecular signature, yet shares several characteristics of brown adipocytes, including high mitochondrial content. When activated, beige fat can be induced to initiate a thermogenic transcriptional program similar to that of BAT. Recent human studies have identified brown and/or beige fat in the supraclavicular region using various radiation imaging modalities. This remarkable discovery has reinvigorated scientific interest in adipose browning and brown/beige fat activation as possible therapeutic targets for obesity. Like in rodents, several groups have previously tested the potential impact of cold exposure and b3-adrenergic agonism on BAT-mediated thermogenesis in humans. However, even though these approaches were shown to significantly increase energy expenditure and promote weight loss in obese individuals, they are not ideal clinical interventions. Cold exposure is uncomfortable and requires prolonged treatment, while b3-adrenergic agonists may lead to many adverse effects like cardiovascular problems. This thesis will evaluate the therapeutic potential and clinical relevance of alternative anti-obesity approaches that target adipose browning and beige adipose activation.

Wu, Hoi Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 92-104). / Abstracts in English and Chinese. / Thesis/ Assessment Committee --- p.i / Declaration --- p.ii / Acknowledgments --- p.vi / Table of Content --- p.vii / List of Abbreviations --- p.x / List of Figures --- p.xiv / List of Tables --- p.xv / Chapter 1. --- Literature Review --- p.1 / Chapter 1.1 --- Introduction of diabetes mellitus --- p.1 / Chapter 1.1.1 --- Definition and prevalence --- p.1 / Chapter 1.1.2 --- Diagnosis and classification --- p.2 / Chapter 1.1.3 --- Symptoms and complications --- p.4 / Chapter 1.1.4 --- Cause and risk factors --- p.5 / Chapter 1.1.5 --- Prevention and treatment --- p.9 / Chapter 1.2 --- The role of adipose tissue in pathophysiology of T2DM --- p.10 / Chapter 1.2.1 --- Randle's glucose-fatty acid hypothesis --- p.11 / Chapter 1.2.2 --- Ectopic fat storage hypothesis --- p.12 / Chapter 1.2.3 --- Adipose tissue as an endocrine organ --- p.13 / Chapter 1.2.4 --- Low-grade inflammation --- p.15 / Chapter 1.2.5 --- Endoplasmic reticulum (ER) stress --- p.17 / Chapter 1.3 --- Use of berberine in the treatment of T2DM --- p.18 / Chapter 1.3.1 --- Efficacy of berberine in treating diabetes --- p.18 / Chapter 1.3.2 --- Berberine on glucose and lipid metabolism of animals --- p.19 / Chapter 1.3.3 --- Inhibition of adipogenesis --- p.20 / Chapter 1.3.4 --- Activation of AMP-Activated Protein Kinase (AMPK) --- p.20 / Chapter 1.3.5 --- Mitochondrial inhibition --- p.21 / Chapter 1.4 --- Introduction of proteomics --- p.21 / Chapter 1.4.1 --- Why proteomics? --- p.22 / Chapter 1.4.2 --- Gel-based proteomics: Two-Dimensional Gel Electrophoresis --- p.23 / Chapter 1.4.3 --- Gel-free proteomics --- p.25 / Chapter 1.4.4 --- Mass spectrometry --- p.26 / Chapter 1.4.5 --- Proteomics as tool for diabetes research --- p.27 / Chapter 1.5 --- Objectives and significance --- p.32 / Chapter 2. --- Materials and Methods --- p.34 / Chapter 2.1 --- Drug preparation --- p.34 / Chapter 2.2 --- Animal experiment --- p.34 / Chapter 2.3 --- Comparison of proteome of visceral white adipose tissue: obese db/db micevs lean m+/db mice and BBR-treated vs control db/db mice --- p.36 / Chapter 2.3.1 --- Protein sample preparation from adipose tissue --- p.36 / Chapter 2.3.2 --- Protein quantitation --- p.37 / Chapter 2.3.3 --- 2D Gel electrophoresis --- p.37 / Chapter 2.3.4 --- Image analysis --- p.39 / Chapter 2.3.5 --- In-gel digestion and MALDI-ToF MS --- p.39 / Chapter 2.4 --- Cell culture experiment --- p.40 / Chapter 2.5 --- Oil Red O staining --- p.42 / Chapter 2.6 --- Glycerol determination --- p.42 / Chapter 2.7 --- Comparison of proteomes of BBR-treated and control 3T3-L1 adipocytes..… --- p.43 / Chapter 2.7.1 --- Protein sample preparation from 3T3-L1 cells --- p.43 / Chapter 2.7.2 --- Protein quantitation --- p.43 / Chapter 2.7.3 --- 2D Gel electrophoresis --- p.44 / Chapter 2.7.4 --- Image analysis --- p.44 / Chapter 2.7.5 --- In-gel digestion and MALDI-ToF MS --- p.44 / Chapter 2.8 --- Western Immunoblotting --- p.44 / Chapter 2.8.1 --- Protein sample preparation of BBR-treated and control 3T3-L1 --- p.44 / Chapter 2.8.2 --- SDS-PAGE --- p.44 / Chapter 2.8.3 --- Protein blotting --- p.45 / Chapter 2.8.4 --- Membrane blocking and antibody incubations --- p.45 / Chapter 2.8.5 --- Detection of Proteins --- p.46 / Chapter 2.9 --- Statistical analysis --- p.46 / Chapter 3. --- Results --- p.47 / Chapter 3.1 --- Comparison of total protein profiles of visceral adipose tissue of obese db/db and lean m+/db mice --- p.47 / Chapter 3.2 --- Effect of berberine on glucose metabolism of obese db/db mice --- p.53 / Chapter 3.3 --- Comparison of the protein profiles of visceral adipose tissue of BBR-treated and control db/db mice --- p.55 / Chapter 3.4 --- Effect of berberine treatment on 3T3-L1 adipocytes --- p.61 / Chapter 3.4.1 --- Berberine treatment inhibited intracellular triglyceride accumulation in both mature and pre-mature 3T3-L1 adipocytes --- p.61 / Chapter 3.4.2 --- Berberine treatment enhanced lipolysis in mature 3T3-L1 adipocytes but inhibited lipolysis in pre-mature 3T3-L1 adipocytes --- p.65 / Chapter 3.4.3 --- Color change in culture media after berberine treatment --- p.65 / Chapter 3.4.4. --- Comparison of protein profiles between berberine-treated and control 3T3-L1 adipocytes --- p.67 / Chapter 3.4.5 --- Western blotting --- p.73 / Chapter 4. --- Discussion --- p.75 / Chapter 4.1 --- Comparison of total protein profiles of visceral adipose tissue of obese db/db and lean m+/db mice --- p.75 / Chapter 4.2 --- "Berberine lowers body weight, reduces fasting blood glucose level and improves glucose-lowering ability of db/db mice" --- p.78 / Chapter 4.3 --- Comparison of the protein profiles of visceral adipose tissue of BBR-treated and control db/db mice --- p.79 / Chapter 4.4 --- Berberine inhibited lipid accumulation in mature and pre-mature 3T3-L1 adipocytes --- p.84 / Chapter 4.5 --- Berberine enhanced lipolysis in mature 3T3-L1 adipocytes but inhibited lipolysis in pre-mature 3T3-L1 adipocytes --- p.84 / Chapter 4.6 --- Comparison of the protein profiles of BBR-treated and control 3T3-L1 adipocytes --- p.85 / Chapter 4.7 --- Western blotting --- p.88 / Chapter 4.8 --- General discussion --- p.89 / Chapter 5. --- References --- p.92

Mutations in the melanocortin 4 receptor (MC4R) are the most frequent cause of monogenetic forms of human obesity. Despite its importance, the MC4R signaling pathways and transcriptional regulation that underly the melanocortin pathway are far from being fully understood. The transcription factor Nescient Helix Loop Helix 2 (Nhlh2), is known to influence the melanocortin pathway. It regulates the transcription of genes by binding to the E-Box binding sites present in the promoter region. Here in this dissertation, Nhlh2's role as a transcriptional regulator of Mc4r and the effects of deletion of Nhlh2 on peripheral energy expenditure, glucose homeostasis and fatty acid oxidation are reported. To investigate the transcriptional mechanisms of Mc4r and the involvement of Nhlh2, gene expression analysis, DNA-protein binding, transactivation assays, and SiRNA induction were used. We show that Nhlh2 regulates the transcription of Mc4r by binding to the three E-Boxes present on the promoter at -553, -361 and +47. Further, SiRNA knockdown of Nhlh2 in the N29/2 cell line depresses Mc4r expression which suggests the requirement of Nhlh2 for Mc4r transcription. Development of adult onset obesity in the absence of evident hyperphagia questions the ability of mice which lacks Nhlh2 (N2KO) to utilize energy substrate efficiently. To test the effect of deletion of Nhlh2 in N2KO, body composition analysis, tissue specific characterization, fatty acid oxidation and glucose and insulin homeostasis were assessed. N2KO mice have a higher fat content than WT at the age of 12 weeks. There are architectural differences in adipose tissue of N2KO. White adipose tissue (WAT) shows infiltration of macrophages, and increased mRNA and serum levels of interleukin 6 which suggests the presence of a systemic inflammatory state in the N2KO mice. Sympathetic nervous system tone is reduced in both brown adipose tissue (BAT) and WAT, as evidenced by gene expression analysis, and this may be because of overall reduced melanocortinergic tone in N2KO mice. N2KO mice have an impaired glucose tolerance on the basis of their late glucose clearance on glucose (non-significant) and insulin (significant) challenges. Fatty acid oxidation (FAO) is higher in red fibers of skeletal muscle, and the respiratory exchange ratio (RER) is lower in N2KO, which is indicative of using fat as a preferential energy source. Increased expression of genes involved in the lipid metabolism in skeletal muscle and liver supports the RER and FAO, and are indicative of high turnover of lipids in N2KO. Findings from these studies implicate Nhlh2 as a transcriptional regulator of Mc4r which has a direct relevance to the ever increasing epidemic of obesity. Characterization of N2KO mice sheds light on the adult onset obesity phenotype. Knowledge gained from these findings will help us understand the monogenetic form of obesity more completely and could lead to the design of improved pharmacological therapies that target Nhlh2 or Mc4r or modify physical activity behavior. / Ph. D.