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

Location: Children's Nutrition Research Center

2021 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 highly palatable food for the enjoyment of eating, which can lead to the consumption of unnecessary calories. Researchers in Houston, Texas, have discovered that 5-hydroxytryptamine (5-HT) neurons can suppress hedonic eating. 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. Additional studies are needed to reveal how the activity of brain 5-HT cells is regulated by nutrient intake and how these cells send signals to the downstream cells to regulate feeding behaviors.

2. Maintaining blood glucose within the normal range is vital for organism health. Elevated blood glucose levels that are above the normal range can lead to serious health compilations such as heart attack, stroke, kidney failure, leg amputation, and vision loss. Scientists in Houston, Texas, have discovered a molecular switch in the brain that determines blood glucose levels. A signaling molecule called Rap1 in the hypothalamus of the brain acts as a determinant of blood glucose. When Rap1 is turned on, blood glucose is elevated. More importantly, when it is off, blood glucose is decreased and corrects diabetic conditions in mice. Researchers will next attempt to identify chemical(s) that can manipulate Rap1 to control our blood glucose, and novel therapeutic opportunities to improve type 2 diabetes from these research efforts.

3. Obesity is not only a peripheral disease but also a group of brain disorders. When energy levels in the body are sensed to be high, fat cells send signals to the brain to inhibit hunger. The failure of this inhibition could cause the occurrence of obesity. Scientists in Houston, Texas, recently found a new neural circuit from the hypothalamus to the hindbrain that could inhibit the activities of neurons in the hindbrain. The effect of activating this neural circuit was enhancing the appetite toward a calorie-enriched high-fat diet, and the inhibition of this neural pathway could reduce feeding behavior accordingly. The long-term treatment on this pathway could help to suppress eating a high-fat diet and reduce weight gain. This work will help researchers gain new knowledge about the mechanisms of eating disorders and provide insights into the functional connection and key signaling components of a novel neural circuit in the control of feeding behaviors.

Review Publications
Liu, H., Xu, Y., Hu, F. 2020. AMPK in the ventromedial nucleus of the hypothalamus: A key regulator for thermogenesis. Frontiers in Endocrinology. 11. Article 578830. https://doi.org/10.3389/fendo.2020.578830.
Fukuda, M. 2021. The role of GIP receptor in the CNS for the pathogenesis of obesity. Diabetes. https://doi.org/10.2337/dbi21-0001.
He, Y., Liu, H., Yin, N., Yang, Y., Wang, C., Yu, M., Liu, H., Liang, C., Wang, J., Tu, L., Zhang, N., Wang, L., He, Y., Fukuda, M., Wu, Q., Sun, Z., Tong, Q., Xu, Y. 2021. Barbadin potentiates long-term effects of lorcaserin on POMC neurons and weight loss. Journal of Neuroscience. 41(26):5734-5746. https://doi.org/10.1523/JNEUROSCI.3210-20.2021.
Zhu, C., Jiang, Z., Xu, Y., Cai, Z., Jiang, Q., Xu, Y., Xue, M., Arenkiel, B., Wu, Q., Shu, G., Tong, Q. 2020. Profound and redundant functions of arcuate neurons in obesity development. Nature Metabolism. 2:763-774. https://doi.org/10.1038/s42255-020-0229-2.
Mohammad, M., Didelija, I., Stoll, B., Nguyen, T., Marini, J. 2021. Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs. American Journal of Physiology. 320(3):E641-E652. https://doi.org/10.1152/ajpendo.00472.2020.
Liu, H., Wang, C., Yu, M., Yang, Y., He, Y., Liu, H., Liang, C., Tu, L., Zhang, N., Wang, L., Wang, J., Liu, F., Hu, F., Xu, Y. 2021. TPH2 in the dorsal raphe nuclei regulates energy balance in a sex-dependent manner. Endocrinology. 162(1):1-16. https://doi.org/10.1210/endocr/bqaa183.
Kim, E., Xu, Y., Cassidy, R., Lu, Y., Yang, Y., Tian, J., Li, D., Drunen, R., Ribas-Latre, A., Cai, Z., Xue, M., Arenkiel, B., Eckel-Mahan, K., Xu, Y., Tong, Q. 2020. Paraventricular hypothalamus mediates diurnal rhythm of metabolism. Nature Communications. 11:3794. https://doi.org/10.1038/s41467-020-17578-7.
Yu, K., He, Y., Hyseni, L., Pei, Z., Yang, Y., Xu, P., Cai, X., Liu, H., He, Y., Yu, M., Liang, C., Yang, T., Wang, J., Gourdy, P., Arnal, J., Lenfant, F., Xu, Y., Wang, C. 2020. 17B-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERa signaling. Molecular Metabolism. 42. Article 101053. https://doi.org/10.1016/j.molmet.2020.101053.
Zhang, Z., Reis, F., He, Y., Park, J., Divittorio, J., Sivakumar, N., Van Veen, E., Maesta-Pereira, S., Shum, M., Nichols, I., Massa, M., Anderson, S., Paul, K., Liesa, M., Ajijola, O., Xu, Y., Adhikari, A., Correa, S. 2020. Estrogen-sensitive medial preoptic area neurons coordinate torpor in mice. Nature Communications. 11:6378. https://doi.org/10.1038/s41467-020-20050-1.
Xia, G., Han, Y., Meng, F., He, Y., Srisai, D., Farias, M., Dang, M., Palmiter, R.D., Xu, Y., Wu, Q. 2021. Reciprocal control of obesity and anxiety-depressive disorder via a GABA and serotonin neural circuit. Molecular Psychiatry. https://doi.org/10.1038/s41380-021-01053-w.
Shi, Y., Zhai, H., Sharon, J., Shen, Y., Ran, Y., Hoang, G., Chen, M. 2021. Gene expression analysis of environmental temperature and high-fat diet-induced changes in mouse supraclavicular brown adipose tissue. Cells. 10(6):1370. https://doi.org/10.3390/cells10061370.
Stypulkowski, E., Feng, Q., Joseph, I., Farrell, V., Flores, J., Yu, S., Sakamori, R., Sun, J., Bandyopadhyay, S., Das, S., Dobrowolski, R., Bonder, E.M., Chen, M., Gao, N. 2021. Rab8 attenuates Wnt signaling and is required for mesenchymal differentiation into adipocytes. Journal of Biological Chemistry. 296:100488. https://doi.org/10.1016/j.jbc.2021.100488.
Kaneko, K., Lin, H.Y., Fu, Y., Saha, P.K., De La Puente-Gomez, A.B., Xu, Y., Ohinata, K., Chen, P., Morozov, A., Fukuda, M. 2021. Rap1 in the VMH regulates glucose homeostasis. Journal of Clinical Immunology Insights (JCI Insights). https://doi.org/10.1172/jci.insight.142545.
Sekizkardes, H., Chung, S.T., Chacko, S., Haymond, M.W., Startzell, M., Walter, M., Walter, P.J., Lightbourne, M., Brown, R.J. 2020. Free fatty acid processing diverges in human pathologic insulin resistance conditions. Journal of Clinical Investigation. 130(7):3592-3602. https://doi.org/10.1172/JCI135431.
Yang, Y., Xu, Y. 2020. The central melanocortin system and human obesity. Journal of Molecular Cell Biology. 12(10):785-797. https://doi.org/10.1093/jmcb/mjaa048.
Wang, C., Zhou, W., He, Y., Yang, T., Xu, P., Yang, Y., Cai, X., Wang, J., Liu, H., Yu, M., Liang, C., Yang, T., Liu, H., Fukuda, M., Tong, Q., Wu, Q., Sun, Z., He, Y., Xu, Y. 2021. AgRP neurons trigger long-term potentiation and facilitate food seeking. Translational Psychiatry. 11. Article 11. https://doi.org/10.1038/s41398-020-01161-1.
Mohammad, M.A., Didelija, I.C., Marini, J.C. 2020. Arginase II plays a central role in the sexual dimorphism of arginine metabolism in C57BL/6 mice. Journal of Nutrition. 150(12):3133-3140. https://doi.org/10.1093/jn/nxaa318.
Mohammad, M., Didelija, I., Stoll, B., Burrin, D.G., Marini, J. 2020. Modeling age-dependent developmental changes in the expression of genes involved in citrulline synthesis using pig enteroids. Physiological Reports. 8(21):e14565. https://doi.org/10.14814/phy2.14565.
Guthrie, G., Stoll, B., Chacko, S., Mohammad, M., Style, C., Verla, M., Olutoye, O., Schady, D., Lauridsen, C., Tataryn, N., Burrin, D.G. 2021. Depletion and enrichment of phytosterols in soybean oil lipid emulsions directly associate with serum markers of cholestasis in preterm PN-fed pigs. Journal of Parenteral and Enteral Nutrition. https://doi.org/10.1002/jpen.2088.