Understanding the pathogenesis of the metabolic syndrome is paramount to eliminating it. Hepatic metabolic dysfunction associated wifh inadequate substrate oxidation, lipid accumulation, and dyslipidemia is a hallmark of metabolic syndrome as it is evident early in its development and is associated with the severity of other symptoms. It has been speculated that liver metabolic dysfunction is a causative step in the natural progression to metabolic syndrome. Despite the central role of liver metabolism to overall """"""""metabolic health,"""""""" the mechanism for its effectiveness in healthy physically active states, the factors responsible for dysfunction, and the means to correct dysfunction are poorly understood. The protocols that comprise the extended funding period focus on three Specific Aims that are a continuation of innovative work conducted in the current funding cycle. The Speciic Aims will test in lean and high fat fed mice whether (a) the activation of hepatic energy sensors (AMPK, sirtuins, hypoxia inducible factors) are protective against insulin resistance; (b) the extracellular matrix conveys a spatial barrier or signaling event that contributes to the impaired energetics and nutrient fluxes of insulin resistance;and (c) the hepatic adaptations to high fat feeding and physical activity are AMPK-dependent. The regulation of hepatic metabolism will be studied using surgical, experimental, and isotopic tools that allow well controlled studies to be conducted in the unstressed conscious mouse. Highly innovative approaches will allow the Aims to be addressed with unprecedented resolution of a spectrum of pathophysiological events. We have developed a new, highly innovative, and comprehensive method for measurement of nutrient fluxes in the liver using stable isotopes of glucose, water, and proprionate. Hepatic ECM will be characterized by using a novel proteomic method designed to focus on the ECM, immunohistochemistry, polysaccharide binding protein, and transmission electron microscopy. The ongoing and planned studies provide mechanisms by which environniental factors (diet and exercise) interact with genes to cause or rescue hepatic metabolic dysregulation. The results of these studies will introduce new avenues to our understanding and treatment of metabolic diseases.

Public Health Relevance

The metabolic syndrome is an epidemic in Western Culture. Hepatic metabolic dysfunction associated with lipid accumulation and dyslipidemia is evident early in its development and is associated with the severity of other symptoms. It has been speculated that liver metabolic dysfunction is a causative step in progression to metabolic syndrome. These studies will define how liver metabolism is regulated in the healthy liver and wherfi .<^itfis of dvsfunction lie in the nathonfinesi.q of metaholic .syndrome, in.siilin resistance, and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK050277-20
Application #
8733152
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Laughlin, Maren R
Project Start
1995-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hughey, Curtis C; James, Freyja D; Bracy, Deanna P et al. (2017) Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice. J Biol Chem 292:20125-20140
Williams, Ashley S; Trefts, Elijah; Lantier, Louise et al. (2017) Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Hepatic Insulin Resistance. Diabetes 66:325-334
Williams, Ashley S; Kang, Li; Zheng, Jenny et al. (2015) Integrin ?1-null mice exhibit improved fatty liver when fed a high fat diet despite severe hepatic insulin resistance. J Biol Chem 290:6546-57
Williams, Ashley S; Kang, Li; Wasserman, David H (2015) The extracellular matrix and insulin resistance. Trends Endocrinol Metab 26:357-66
Trefts, Elijah; Williams, Ashley S; Wasserman, David H (2015) Exercise and the Regulation of Hepatic Metabolism. Prog Mol Biol Transl Sci 135:203-25
Hasenour, Clinton M; Wall, Martha L; Ridley, D Emerson et al. (2015) Mass spectrometry-based microassay of (2)H and (13)C plasma glucose labeling to quantify liver metabolic fluxes in vivo. Am J Physiol Endocrinol Metab 309:E191-203
Kang, Li; Dai, Chunhua; Lustig, Mary E et al. (2014) Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice. Diabetes 63:3699-710
Hughey, Curtis C; Wasserman, David H; Lee-Young, Robert S et al. (2014) Approach to assessing determinants of glucose homeostasis in the conscious mouse. Mamm Genome 25:522-38
Hasenour, Clinton M; Ridley, D Emerson; Hughey, Curtis C et al. (2014) 5-Aminoimidazole-4-carboxamide-1-?-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J Biol Chem 289:5950-9
von Wilamowitz-Moellendorff, Alexander; Hunter, Roger W; GarcĂ­a-Rocha, Mar et al. (2013) Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis. Diabetes 62:4070-82

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