Research Project: Molecular, Cellular, and Regulatory Aspects of Obesity Development

Location: Children's Nutrition Research Center

2020 Annual Report

Objectives
Obesity and its associated metabolic disorders represent a serious health problem to our society. To address this researchers aim to: 1) determine if potassium channels (SK3) expressed by serotonin neurons are required to regulate feeding behavior and body weight balance using a Cre-loxP strategy to generate mouse models that either lack SK3 selectively in serotonin neurons and test if these manipulations in mice alter animals' food intake and body weight; 2) identify downstream neural circuits that mediate serotonin neuron actions to regulate feeding behavior and body weight balance and selectively stimulate specific downstream neural circuits that originate from brain serotonin neurons in mice, and measure effects on animals' feeding behavior and body weight; 3) identify upstream and downstream signaling molecules of glycogen synthase kinase 3 beta that controls suppressor of cytokine signaling 3 levels and cellular insulin and leptin actions in the hypothalamus by using an ex vivo brain slice model; 4) determine if each component of the glycogen synthase kinase 3 beta-related pathway determines hypothalamic levels of suppressor of cytokine signaling 3 and hypothalamic leptin and insulin actions in vivo by using genetically engineered mouse models; 5) determine the physiological roles of genetically defined Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit in differential control of feeding behavior and energy metabolism; 6) determine the physiological roles of key gamma amino butyric acid and N-methyl-D-aspartic acid glutamate receptor subunits expressed in the Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit for the regulation of appetite, energy balance, and development of obesity; 7) investigate the interaction of various phospholipid species with the LRH-1 nuclear receptor, and determine the potential metabolic benefits to insulin resistance in obesity; 8) use transgenic mice with liver specific knockout of the liver receptor homolog LRH-1 nuclear receptor to critically test its role as the potential mediator of the metabolic benefits of phosphatidylcholine agonist ligands in obesity; 9) removed due to investigator departure; 10) removed due to investigator departure; 11) determine if maternal obesity and high-fat diet during gestation induce adipogenic and metabolic program alterations in Wt1 expressing white adipocyte progenitor cells during development; 12) assess if carbohydrate response element binding protein alters macrophage intracellular metabolism and inflammatory response; 13) assess if macrophage carbohydrate response element binding protein activity affects adipose tissue inflammation and the development of diet-induced obesity and insulin resistance; and 14) use wild type mice to determine organ specific metabolism of fatty acids of varying carbon chain lengths, and study their effects on the progression and/or treatment of diet-induced obesity and its related metabolic disorders.

Approach
A multi-discipline approach will be undertaken to address these concerns. Rodent models will be utilized to examine the role of small-conductance Ca2+-activated K+ currents in 5-HT neurons in the regulation of hedonic feeding and we will work to identify a previously unrecognized neural signaling pathway that controls leptin and insulin actions in the hypothalamus and mediates whole-body energy balance. Collectively, the studies will demonstrate the potential roles of metabolic cues (hormones/nutrients), central nervous system circuits, and the intra-neuronal signals in the control of energy and glucose homeostasis. Our research results should identify rational targets for the treatment or prevention of obesity and diabetes. Researchers will also study the role of endogenous phosphatidylcholines in the prevention and treatment of non-alcoholic fatty liver disease and insulin resistance, and test the hypothesis that beneficial effects of these natural phosphatidylcholines are due to LRH-1 activation. We will also will use mouse models of diet-induced obesity and will focus on three general problems associated with obesity: the developmental effects of maternal obesity on offspring adiposity, adipose tissue inflammation that may lead to medical complications, and the effects of dietary fatty acid composition on obesity.

Progress Report
To review the progress made during the year, please refer to the following projects: 3092-51000-064-01S (Project #1), 3092-51000-064-02S (Project #2), and 3092-51000-062-05S (Project #3).

Accomplishments
1. Discovery of a brain cell type that controls hedonic eating. Hedonic eating behavior is a pleasure-driven type of overeating that occurs when an individual consumes food for the enjoyment of eating and this can lead to the consumption of unnecessary calories. Investigators at Houston, Texas, have discovered that a certain type of brain cell, called 5-hydroxytryptamine (5-HT), can suppress hedonic feeding. Since overeating highly palatable foods (often processed foods with high amounts of sugar, fats, and salt) is associated with obesity, a better understanding of the mechanisms by which brain 5-HT cells repress hedonic feeding will provide a framework to target these cells as a potential therapeutic strategy for the prevention or treatment of obesity.

2. Understanding the brain's role in the control of appetite and metabolism. Little is known about how the brain is functionally organized towards the control of hunger and energy metabolism. Researchers in Houston, Texas, recently identified a specific group of nerve cells that regulate feeding and nutrient sensing. Our research suggests that these cells precisely regulate body weight via a balanced control of various peripheral metabolic signals. Genetic mice with deficiency in these cells show uncontrolled overeating and eventually became obese. Conversely, stimulation of the neural signaling within the same group of cells reduces food intake whereas energy expenditure is enhanced, which together lead to a profound weight loss. Overall, the discovery of a group of nerve cells acting as a switch gating the caloric intake would accelerate the development of novel anti-obesity medication.

3. A new mechanism for control of food metabolism in liver. Liver receptor homolog-1 (LRH-1) is a receptor protein that regulates the ability of the liver to respond appropriately to food, to help in digestion and to make energy. Previous studies identified a specific kind of fat, called phosphatidylcholine (PC), which serves to activate the functions associated with LRH-1. In the liver, different PC molecules are made by two different processes. Scientists in Houston, Texas, performed an experiment to see if blocking either of the pathways would lower the activity of LRH-1 and found that blocking one of the pathways decreased LRH-1 function, which also impacted the ability of cells to turn food into energy. These results uncover a new mechanism for the control of food metabolism in the liver by a fat signal that is made within the liver.

Review Publications
Couturier, J., Nuotio-Antar, A.M., Agarwal, N., Wilkerson, G.K., Saha, P., Kulkarni, V., Lakhashe, S.K., Esquivel, J., Nehete, P.N., Ruprecht, R.M., Sastry, J., Meyer, J.M., Hill, L.R., Lake, J.E., Balasubramanyam, A., Lewis, D.E. 2019. Lymphocytes upregulate CD36 in adipose tissue and liver. Adipocyte. 8(1):154-163. https://doi.org/10.1080/21623945.2019.1609202.
Hou, R., Cole, S.A., Graff, M., Haack, K., Laston, S., Comuzzie, A.G., Mehta, N.R., Ryan, K., Cousminer, D.L., Zemel, B.S., Grant, S.A., Mitchell, B.D., Shypailo, R.J., Gourlay, M.L., North, K.E., Butte, N.F., Voruganti, V. 2020. Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal site in Hispanic children. Bone. 132:115175. https://doi.org/10.1016/j.bone.2019.115175.
Wooton-Kee, C., Robertson, M., Zhou, Y., Dong, B., Sun, Z., Kim, K., Liu, H., Xu, Y., Putluri, N., Saha, P., Coarfa, C., Moore, D.D., Nuotio-Antar, A.M. 2020. Metabolic dysregulation in the Atp7b -/- Wilson's disease mouse model. Proceedings of the National Academy of Sciences. 117(4):2076–2083.
Zhang, W., Wu, X., Pei, Z., Kiess, W., Yang, Y., Xu, Y., Chang, Z., Wu, J., Sun, C., Luo, F. 2019. GDF5 promotes white adipose tissue thermogenesis via p38 MAPK signaling pathway. DNA and Cell Biology 38(11):1303-1312. https://doi.org/10.1089/dna.2019.4724
Hua, X., Wang, Y., Jia, P., Xiong, Q., Hu, Y., Chang, Y., Lai, S., Xu, Y., Zhao, Z., Song, J. 2020. Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression. BMC Complementary and Alternative Medicine. 18(1):2 https://doi.org/10.1186/s12916-019-1469-4
Cassidy, R., Lu, Y., Jere, M., Tian, J., Xu, Y., Mangieri, L.R., Felix-Okoroji, B., Selever, J., Xu, Y., Arenkiel, B.R., Tong, Q. 2019. A lateral hypothalamus to basal forebrain neurocircuit promotes feeding by suppressing responses to anxiogenic environmental cues. Science Advances. 5(3):1640 https://doi.org/10.1126/sciadv.aav1640
Xu, Y., Lu, Y., Cassidy, R.M., Mangieri, L.R., Zhu, C., Huang, X., Jiang, Z., Justice, N.J., Xu, Y., Arenkiel, B.R., Tong, Q. 2019. Identification of a neurocircuit underlying regulation of feeding by stress-related emotional responses. Nature Communications. 10(1):3446 https://doi.org/10.1038/s41467-019-11399-z
Qu, N., He, Y., Wang, C., Xu, P., Yang, Y., Cai, X., Liu, H., Yu, K., Pei, Z., Hyseni, L., Sun, Z., Fukuda, M., Li, Y., Tian, Q., Xu, Y. 2019. A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia. Molecular Psychiatry. 25:1006-1021. https://doi.org/10.1038/s41380-019-0506-1.
Choi, S., Dong, B., Lin, C.J., Heo, M., Kim, K., Sun, Z., Wagner, M., Putluri, N., Jae Myoung, S., Wang, M.C., Moore, D.D. 2020. Methyl-sensing nuclear receptor liver receptor homolog-1 regulates mitochondrial function in mouse hepatocytes. Hepatology. 71(3):1055-1069. https://doi.org/10.1002/hep.30884.
Fu, Y., Kaneko, K., Lin, H.Y., Mo, Q., Xu, Y., Suganami, T., Ravn, P., Fukuda, M. 2020. Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus. Endocrinology. https://doi.org/10.1210/endocr/bqaa102.
Call, L., Molina, T., Stoll, B., Guthrie, G., Chacko, S., Plat, J., Robinson, J., Lin, S., Vonderohe, C., Mohammad, M., Kunichoff, D., Cruz, S., Lau, P., Premkumar, M., Nielsen, J., Fang, Z., Olutoye, O., Thymann, T., Britton, R., Sanglid, P., Burrin, D.G. 2020. Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs. Journal of Lipid Research. https://doi.org/10.1194/jlr.RA120000652.
Workeneh, B., Moore, L.W., Fong, J., Shypailo, R., Gaber, A., Mitch, W.E. 2019. Successful kidney transplantation is associated with weight gain from truncal obesity and insulin resistance. Journal of Renal Nutrition. 29(6):548-555. https://doi.org/10.1053/j.jrn.2019.01.009.
He, Y., Xu, P., Wang, C., Yan, X., Yu, M., Yang, Y., Yu, K., Cai, X., Qu, N., Saito, K., Wang, J., Hyseni, L., Robertson, M., Piyarathna, B., Gao, M., Khan, S., Liu, F., Chen, R., Coarfa, C., Zhao, Z., Tong, Q., Sun, Z., Xu, Y. 2020. Estrogen receptor-a expressing neurons in the ventrolateral VMH regulate glucose balance. Nature Communications. 11:2165. https://doi.org/10.1038/s41467-020-15982-7
Zhu, C., Jiang, Z., Xu, Y., Cai, Z., Jiang, Q., Xu, Y., Xue, M., Arenkiel, B., Wu, Q., Shu, G., Lu, Y., Tong, Q. 2020. Profound and redundant functions of arcuate neurons in obesity development. Nature Metabolism. https://doi.org/10.1038/s42255-020-0229-2.
Sun, Z., Xu, Y. 2020. Nuclear receptor coactivators (NCOAs) and corepressors (NCORs) in the brain. Endocrinology. 161(8):1-12. https://doi.org/10.1210/endocr/bqaa083.
Shypailo, R.J., Wong, W.W. 2020. Fat and fat-free mass index references in children and young adults: Assessments along racial and ethnic lines. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqaa128.
Zhu, C., Xu, Y., Jiang, Z., Tian, J., Cassidy, R.M., Cai, Z., Shu, G., Xu, Y., Xue, M., Arenkiel, B., Jiang, Q., Tong, Q. 2020. Disrupted hypothalamic CRH neuron responsiveness contributes to diet-induced obesity. EMBO Reports. 21:e49210. https://doi.org/10.15252/embr.201949210.