The liver is central to mammalian metabolism and plays a critical role in providing fuel to other tissues particularly when food is limiting. People with disparate inborn errors in mitochondrial fatty acid ?-oxidation exhibit life-threatening hypoketotic-hypoglycemia following a fast due to the critical role of fatty acid oxidation to gluconeogenesis and ketogenesis. To understand the contribution of hepatic fatty acid oxidation to systemic metabolic dysfunction, we have generated mice that cannot oxidize long chain fatty acids via mitochondrial ?-oxidation specifically in hepatocytes by the conditional deletion of Carnitine Palmitoyltransferase 2 (Cpt2), an obligate step encoded by a single gene. Here we will leverage this model to understand the contribution of fatty acid oxidation to hepatic and extrahepatic regulation of systemic metabolic homeostasis during fasting and high fat dietary challenges. Herein we propose three specific aims. 1. Determine the requirements of hepatic fatty acid oxidation during fasting. 2. Determine the role of hepatic fatty acid oxidation in high fat diet- induced body weight and glucose tolerance. 3. Determine the mechanism of fatty acid-induced transcription. The long-term goal is to understand the roles and requirements of hepatic lipid metabolism during fasting and high fat feeding. The expectation is that our proposed studies will describe the requirements of hepatic fatty acid oxidation in fasting and the development of obesity and glucose intolerance. Additionally, we will uncover new rolls for hepatokines and metabolic signaling in the control of systemic metabolic physiology.

Public Health Relevance

The rationale for these studies is that understanding the roles and requirements of hepatic fatty acid oxidation in fasting and high fat feeding will provide insight into basic liver physiology and also for the obesity and glucose intolerance which exhibits defects in hepatic lipid metabolism. Determining the systemic communication by the liver to signal mitochondrial dysfunction in response to disparate modalities of lipid overload may lead to novel therapeutic interventions for obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK116746-03
Application #
9959186
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Teff, Karen L
Project Start
2018-09-22
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205