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Mesoderm specific transcript and adipose tissue expansion

Award Number: R01DK120844
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/22/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Mesoderm specific transcript and adipose tissue expansion - The rising global rate of obesity is caused by complex interactions between genetic, environmental and epigenetic factors. Gene-environment interactions are recognized as important for the development of obesity; however, the contribution of epigenetic-based mechanisms is not well defined. Using a diet-induced obesity susceptible genetically identical population of mice raised in controlled environmental conditions, we were able to identify potential epigenetic determinants of obesity. One of the genes that was identified, the paternally-expressed gene mesoderm specific transcript (Mest), was shown to have highly variable expression in white adipose tissue (WAT) and was positively associated with WAT expansion. Mouse strains developed by our laboratory with global and adipose tissue-specific inactivation of Mest showed that its inactivation is able to reduce high fat diet-mediated adipose tissue expansion and WAT inflammation, and improve glucose tolerance and insulin sensitivity. The stability of inter-individual variations of Mest expression in WAT is predictive for the development of obesity and suggestive of a `heritable' epigenetic mechanism for its regulation. Because Mest is coordinately regulated with the transcriptional activator Kruppel-like-factor 14 (Klf14) which resides ~200 kb downstream of the Mest locus on mouse Chr 6, it is possible that both genes are regulated by a common epigenetic pathway during metabolic imbalance. One of the goals of this proposal is to test whether Mest is regulated by an epigenetically heritable regulatory network that controls its expression in adipose tissue with dietary obesity (Aim 1). MEST belongs to the α/β hydrolase family of proteins which has a diversity of catalytic functions. Based on homology with similar proteins, MEST may function as an acyltransferase, lipase or epoxide hydrolase. We showed that MEST is localized within the endoplasmic reticulum (ER) membrane of adipocytes and co-localizes with lipid droplet surface proteins at ER-lipid droplet contact points. In vitro studies using mesenchymal progenitor cells derived from control or Mest-null mice, in concert with shRNA knockdown of Gpat4 suggest that MEST either possesses endogenous GPAT-like catalytic activity, or is an allosteric regulator of GPAT function. A second goal of this proposal will be to define how MEST functions to facilitate lipid accumulation in adipocytes (Aim 2). The aims of this proposal test our hypothesis that an epigenetic mechanism common to both Mest and Klf14 controls their expression in adipose tissue, and that inter-individual susceptibility for the development of obesity and impaired glucose homeostasis is caused by MEST-facilitated lipid accumulation in adipocytes via modulation of GPAT or EH activity at the ER-lipid droplet interface.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $441,701 )
2021	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/12/2021	NON-COMPETING CONTINUATION	$441,701
2021	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $441,701

Issue Date FY: 2020 ( Subtotal = $441,701 )
2020	2020	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/24/2020	NON-COMPETING CONTINUATION	$441,701
														Subtotal = $441,701

Issue Date FY: 2019 ( Subtotal = $430,000 )
2019	2019	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/22/2019	NEW	$430,000
														Subtotal = $430,000

Grand Total All Awards = $1,313,402

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Mesoderm specific transcript and adipose tissue expansion

Award Number: R01DK120844

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/22/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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