Obesity is a major health problem worldwide and also a leading risk factor for various diseases, including type 2 diabetes, stroke, and cardiovascular diseases. Since neuronal activities in the brain are critical for maintaining systemic energy homeostasis, abnormal neuronal functions could lead to the development of obesity; thus, unraveling the complex neuronal mechanisms behind the central control of energy homeostasis is a high priority if we are to understand the biology of obesity and eventually treat or alleviate the health burdens it imposes. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified neurotrophic factor whose protective efficacy has been confirmed in several neurodegenerative diseases, but its endogenous function in the brain remains largely unknown. Recently, we generated a transgenic mouse model in which MANF is overexpressed in the central nervous system. Surprisingly, MANF transgenic mice become obese and exhibit hyperphagia. Moreover, we found endogenous MANF is highly enriched in the hypothalamus, and its expression is closely linked to the feeding status of the mice. These observations led us to hypothesize that MANF is involved in the hypothalamic control of food intake and energy homeostasis.
Specific Aims for testing this hypothesis are:
Aim (1) To evaluate the phenotypes of mice by increasing or reducing MANF expression in the hypothalamus. We will use virus transduction and CRISPR/Cas9 technology to modulate MANF levels specifically in the hypothalamus and evaluate the metabolic phenotypes of the mice after such modulations;
Aim (2) To identify hypothalamic MANF partners in the regulation of energy homeostasis. We will perform affinity purification chromatography followed by tandem mass spectrometry to comprehensively study the MANF interactome in the hypothalamus and how such interactions shape the function of MANF. The results of this study will broaden our knowledge about the neuronal functions that regulate energy homeostasis. Understanding the molecular mechanisms of MANF signaling will yield valuable insights for developing potential MANF-based therapeutic strategies to treat obesity and related neurodegenerative disorders. !

Public Health Relevance

We found that transgenic mice overexpressing mesencephalic astrocyte-derived neurotrophic factor (MANF) develop obesity. We will investigate whether the altered expression of MANF in the hypothalamus accounts for the obesity phenotype and what is the mechanism behind the hypothalamic function of MANF.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS102913-02
Application #
9533710
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
He, Janet
Project Start
2017-08-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Yang, Su; Li, Shihua; Li, Xiao-Jiang (2018) MANF: A New Player in the Control of Energy Homeostasis, and Beyond. Front Physiol 9:1725
Guo, Jifeng; Cui, Yiting; Liu, Qiong et al. (2018) Piperine ameliorates SCA17 neuropathology by reducing ER stress. Mol Neurodegener 13:4
Yang, Su; Yang, Huiming; Chang, Renbao et al. (2017) MANF regulates hypothalamic control of food intake and body weight. Nat Commun 8:579