Aging is associated with a progressive decline of metabolic health and represents a unique risk factor for the development of type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease in the elderly. The biology underlying age-related metabolic disease is likely multifaceted, and conceptually, may involve intrinsic changes in tissue metabolism and perturbations of inter-tissue metabolic crosstalk. Endocrine factors play a critical role in modulating carbohydrate and lipid metabolism and maintaining systemic energy homeostasis. Perturbations of endocrine signaling are commonly observed during mammalian aging. However, the nature of endocrine signals that govern metabolic homeostasis during mammalian aging remains poorly defined. In preliminary studies, we identified Neuregulin 4 (Nrg4) as a novel adipocyte-derived secreted factor that protects mice from insulin resistance and hepatic fat accumulation in an age-dependent manner. The expression of Nrg4 in mouse adipose tissues was elevated by caloric restriction. These findings form the basis for our central hypothesis that endocrine signaling by adipokines plays a uniquely important role in preserving metabolic homeostasis during aging. In this proposal, we plan to evaluate the physiological role of this factor in age-dependent metabolic regulation using gain- and loss-of-function mouse models. We will delineate its regulation during aging and explore the molecular and metabolic mechanisms involved.

Public Health Relevance

Aging is associated with a progressive deterioration of metabolic health that markedly increases the risk for type 2 diabetes and cardiovascular disease. Despite this, our understanding of the molecular and physiological mechanisms underlying metabolic homeostasis in the context of aging remains very limited. The overall goals of this project are to elucidate the significance of a novel adipose-liver endocrine pathway in maintaining metabolic homeostasis during aging and to explore the unique mechanisms underlying age-dependent metabolic regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG055379-01
Application #
9277806
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Fuldner, Rebecca A
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Peng; Kuang, Henry; He, Yanlin et al. (2018) NRG1-Fc improves metabolic health via dual hepatic and central action. JCI Insight 3:
Chen, Xiao-Wei; Li, Siming; Lin, Jiandie D (2017) The Micro-Managing Fat: Exosomes as a New Messenger. Trends Endocrinol Metab 28:541-542
Chen, Zhimin; Wang, Guo-Xiao; Ma, Sara L et al. (2017) Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol Metab 6:863-872
Guo, Liang; Zhang, Peng; Chen, Zhimin et al. (2017) Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J Clin Invest 127:4449-4461