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'Metabolically Activated' Macrophages in Obesity and Insulin Resistance

Award Number: R01DK102960
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: 05/05/2015
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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'Metabolically Activated' Macrophages in Obesity and Insulin Resistance - ABSTRACT Visceral obesity associates with insulin resistance and chronic inflammation, which are major risk factors for the metabolic syndrome, diabetes, and cardiovascular disease. Although the cellular hallmark of obesity is neutral lipid expansion in adipocytes, adipose tissue of obese mice and humans also accumulate macrophages and other leukocytes. It is well accepted that adipose tissue macrophages (ATMs) play a critical role in systemic insulin resistance, suggesting that inflammatory mediators produced by ATMs are important factors linking excess fat mass to insulin sensitivity, glucose intolerance, and increased atherosclerotic risk. Understanding the mechanistic basis of the pro-inflammatory ATM phenotype and ATM function is required to devise new strategies for attenuating inflammation in metabolic disease. Pro-inflammatory pathways in ATMs are commonly attributed to classical activation (exposure to bacteria, M1), establishing molecular links between innate immunity and metabolic dysfunction. Recent studies, including work from our lab, suggest that M1 activation fails to accurately represent the complex phenotype of ATMs in vivo. We have shown that ATMs in obese adipose tissue from humans and mice adopt a unique ‘metabolically activated’ (MMe) phenotype that is distinct from the M1 phenotype. Inhibiting MMe activation of macrophages in vivo, attenuates ATM inflammation and improved glucose tolerance in mice. Moreover, the abundance of MMe-like ATMs in visceral fat is positively correlated with insulin resistance in patients controlled for adiposity. These findings underscore the pathophysiological importance of MMe macrophages in mice and humans. Although MMe and M1 macrophages are both characterized by increased expression of NFkB-induced inflammatory cytokines (ie. Tnfa, Il1b, Il6), our preliminary studies demonstrate that the upstream signaling cascades driving NFkB activation are remarkably distinct. We provide evidence for a novel fatty acid-driven, ROS-dependent, tyrosine-kinase mediated, pro-inflammatory signaling cascade in MMe macrophages. Targeting this ‘metabolically activated NFkB’ (Me-NFkB) pathway at any point selectively attenuates inflammatory cytokine expression by MMe macrophages. Our work has positioned us to test the innovative hypothesis that this Me-NFkB pathway promotes ATM inflammation and insulin resistance during obesity but is dispensable for inflammation required for host defense during infection. Specifically, we plan to 1) Delineate the Me-NFkB pathway that drives inflammation in MMe macrophages, and 2) Determine if targeting the Me-NFkB pathway improves insulin sensitivity in mice. Overall, our proposed studies aim to demonstrate that macrophage inflammation in metabolic disease can be attenuated without blocking these same cytokines in bacterial infection, a conceptual milestone that may lead to an improved anti-inflammatory strategy in the clinic.


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 = $490,784 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	12/20/2023	NON-COMPETING CONTINUATION	$460,110
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	5/6/2024	NON-COMPETING CONTINUATION	$30,674
														Subtotal = $490,784

Issue Date FY: 2023 ( Subtotal = $511,233 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	1/5/2023	NON-COMPETING CONTINUATION	$511,233
														Subtotal = $511,233

Issue Date FY: 2022 ( Subtotal = $535,192 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	3/28/2022	NON-COMPETING CONTINUATION	$53,520
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	11/11/2021	NON-COMPETING CONTINUATION	$481,672
														Subtotal = $535,192

Issue Date FY: 2021 ( Subtotal = $565,866 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	12/16/2020	COMPETING CONTINUATION	$559,065
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	12/23/2020	COMPETING CONTINUATION	$6,801
2021	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/8/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $565,866

Issue Date FY: 2019 ( Subtotal = $450,080 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/17/2019	NON-COMPETING CONTINUATION	$450,080
														Subtotal = $450,080

Issue Date FY: 2018 ( Subtotal = $450,080 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/9/2018	NON-COMPETING CONTINUATION	$450,080
														Subtotal = $450,080

Issue Date FY: 2017 ( Subtotal = $453,164 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/15/2017	NON-COMPETING CONTINUATION	$45,316
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/18/2017	NON-COMPETING CONTINUATION	$407,848
														Subtotal = $453,164

Issue Date FY: 2016 ( Subtotal = $454,858 )
2016	2016	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/13/2016	NON-COMPETING CONTINUATION	$454,858
														Subtotal = $454,858

Issue Date FY: 2015 ( Subtotal = $476,289 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/4/2015	NEW	$476,289
														Subtotal = $476,289

Grand Total All Awards = $4,387,546

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'Metabolically Activated' Macrophages in Obesity and Insulin Resistance

Award Number: R01DK102960

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: 05/05/2015

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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