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ANT2 in metaflammation and insulin resistance

Award Number: R01DK124298
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: 12/16/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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ANT2 in metaflammation and insulin resistance - PROJECT SUMMARY/ABSTRACT The prevalence of Type 2 diabetes mellitus (T2DM) is rising dramatically on a global basis and has now reached epidemic proportions. Current anti-diabetic therapeutics are available, but are inadequate to fully control T2DM in most patients, resulting in a great deal of morbidity and mortality. Insulin resistance is a major etiologic cause underlying T2DM. However, there are no clinical options to directly improve insulin sensitivity, except for thiazolidinediones, which are infrequently used due to unwanted side effects. Obesity is the most common cause of insulin resistance, and accumulating evidence indicates that obesity-induced inflammation (or metaflammation) is an important cause of insulin resistance and obesity- associated metabolic complications. Therefore, there are huge unmet medical needs for the prevention and treatment of metaflammation. However, it is not known how chronic metaflammation is initiated and propagates during the development of obesity, and why it is not resolved. Macrophages are the major immune cell type mediating metaflammation, and evidence suggest that changes in macrophage mitochondria activity can promote pro-inflammatory activation and M1-like polarization of macrophages. However, how mitochondrial activity is regulated during the course of M1- or M2-like macrophage polarization, especially in the obese/energy-excess adipose tissue microenvironment is not clearly understood. We will tackle the question of obesity-induced metaflammation from a new angle, focusing on mitochondrial biology with a novel target and hypothesis. Our preliminary suggest that ANT2 is a mitochondrial sensor of FFAs in macrophages to induces mitochondria remodeling favoring pro- inflammatory activation. Since the major source of increased plasma FFAs in obesity is adipocytes, FFA- induced ANT2 activation can provide an adipose tissue-specific pro-inflammatory macrophage activation mechanism in obesity. Interestingly, the effect of macrophage ANT2 KO includes the changes in mitochondrial number, mass, and capacity, whereas adipocyte or myocyte ANT2 KO does not cause these changes. This suggest that macrophage ANT2 mediates mitochondria remodeling through a cell type-specific mechanism that is distinct from ANT2 effects in adipocytes and myocytes. We will explore whether macrophage ANT2 mediates the initiation and/or maintenance of metaflammation in obese adipose tissue. We will then assess how ANT2 regulates mitochondrial capacity, dynamics, and metabolism to support the pro-inflammatory activation of macrophages, and how macrophage ANT2 activation induces insulin resistance. If successful, our studies will provide a novel mechanism for how obesity induces tissue-selective metaflammation and insulin resistance. Successful completion of the proposed study will identify ANT2 as a potential target for novel therapeutics to prevent metaflammation, insulin resistance, and glucose intolerance.


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: 2025 ( Subtotal = $355,501 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	11/27/2024	NON-COMPETING CONTINUATION	$355,501
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	12/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $355,501

Issue Date FY: 2024 ( Subtotal = $379,200 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/28/2023	NON-COMPETING CONTINUATION	$355,501
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/6/2024	NON-COMPETING CONTINUATION	$23,699
														Subtotal = $379,200

Issue Date FY: 2023 ( Subtotal = $395,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/1/2022	NON-COMPETING CONTINUATION	$355,501
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/31/2023	NON-COMPETING CONTINUATION	$39,499
														Subtotal = $395,000

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/28/2022	NON-COMPETING CONTINUATION	$39,499
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/11/2021	NON-COMPETING CONTINUATION	$355,501
														Subtotal = $395,000

Issue Date FY: 2021 ( Subtotal = $394,271 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/16/2020	NEW	$394,271
														Subtotal = $394,271

Grand Total All Awards = $1,918,972

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ANT2 in metaflammation and insulin resistance

Award Number: R01DK124298

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: 12/16/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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