This proposal outlines an integrated training and research plan for Dr. Yi Zhu to complete further academic training under the mentorship of Dr. Philipp E. Scherer and transition to an independent investigator specializing in the research field of Connexin43 (Cx43) biology in metabolic adaptation. The overall objective of the research proposal is to understand the multifaceted roles of Connexin43 in the regulation of hepatic FGF21 secretion during fasting as well as its role in adipose tissue ?beiging? during cold exposure. Obesity and diabetes remain a great burden to our society, and current medicines for obesity and diabetes have fell short of achieving treatment goals. So it is important to discover novel pathways that can be leveraged in combating obesity and diabetes. Recently, I have identified that Cx43 channels are implicated in the propagation of sympathetic neuronal outputs from cold exposure in adipose tissue. Systemic Cx43 overexpression in several metabolic tissues improves glucose tolerance and elevates circulating FGF21 levels in mice, a hormone with pleiotropic metabolic actions and holds great potential to be developed into a medication. So I generated several new mouse lines to further study the crosstalk between Connexin43 and FGF21, focusing on metabolic consequences of Connexin43 in liver and adipose tissues in vivo:
Aim 1 investigates the role of Connexin43 gap junction channel in glucagon-stimulated hepatic FGF21 secretion during fasting, and also explore the mechanism by which Connexin43 regulates FGF21 expression.
Aim 2 follows up on a new observation that Connexin43 translocates into beige adipocyte mitochondria during cold exposure, and tests the hypothesis that mitochondrial translocated Cx43 mediates UCP1-independent uncoupling in beige adipocytes. These proposed studies will expand our knowledge on Connexin43 in liver and adipose tissue, and guide us in pharmacologically targeting Cx43 for metabolic diseases, at the channel, the hemichannel, or simply the transcription levels. Under the auspices of the University of Texas Southwestern Medical Center, I will be mentored by internationally recognized leaders in the metabolism field, which will aid the transition of my research career toward an independent investigator position.

Public Health Relevance

Connexin43 exerts multifaceted functions in different metabolic organs. This study aims to reveal the mechanisms and functions of Connexin43 in hepatic FGF21 secretion and adipose tissue ?beiging,? and to test whether modulation of Connexin43 in metabolic tissues could exert protection to metabolic insults. This will provide novel insights into gap junction dependent and independent roles of Connexin43 in regulating hepatic and adipose physiology, and guide clinical development of Connexin43 activators as novel therapies for obesity, diabetes, and relevant metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
4R00DK114498-03
Application #
10056398
Study Section
Special Emphasis Panel (NSS)
Program Officer
Teff, Karen L
Project Start
2019-12-01
Project End
2022-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030