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LIFR-alpha/JAK/STAT3-dependent Adipose Inflammation Contributes to Obesity-Associated NAFLD - Resubmissi

Award Number: R01DK128166
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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LIFR-alpha/JAK/STAT3-dependent Adipose Inflammation Contributes to Obesity-Associated NAFLD - Resubmissi - ABSTRACT Although adipose inflammation is associated with obesity, its role in reprogramming adipocytes and other cells in adipose towards the development of obesity’s metabolic comorbidities including steatosis remain unclear. The complex intracellular (stromal, vascular, immune, and adipocyte) interactions within adipose tissue ultimately regulate its size by balancing adipocyte triacylglyceride (TAG) lipolysis and synthesis. The inflammatory signaling of and between these cell types may also influence adipocyte responses to cAMP modulators. To understand the convergence of these interactions, we previously identified cytokine leukemia inhibitory factor (LIF) as a secretory molecule that increased adipose inflammation and lipolysis. Wild type mice on a high fat diet (HFD) demonstrated 7-fold higher LIF and IL-6 adipose mRNA than matched animals on normal diets. When recombinant LIF was administered to wild-type mice, it caused >50% loss of fat mass through JAK/STAT3- dependent reprogramming of adipose tissue, increasing lipolysis and amplifying inflammation by altering the expression of other cyto/adipokines. JAK inhibitor treatment of rLIF-administered mice suppressed adipose loss through 1) inhibition of adipose inflammation as determined by decreased STAT3 phosphorylation, 2) decreased adipocyte lipolysis, and 3) inhibition of cyto/adipokine changes. To establish the importance of this signaling pathway to adipose inflammation, we selectively silenced LIF receptor (LIFR-α, gene LIFR) or STAT3 in adipocytes and assessed murine development in diet-induced obesity. Both models had decreased adipose inflammation resulting in a 50% increase in adipose mass and a ~75% reduction in total hepatic TAG levels compared to controls, limiting non-alcoholic fatty liver disease (NAFLD) and steatohepatitis in these mice. Conversely, with adipocyte silencing of the JAK/STAT counter-regulator SOCS3 in mice on HFDs, we observed the opposite phenotype with a ~30% reduction in adipose mass compared to controls. We hypothesize that a LIFR-α/JAK/STAT3-dependent Cytokine-Adipose-Hepatic Axis facilitates adipose inflammation, leading to increased lipolysis and altered expression of other cyto/adipokines. The activation of this axis limits adipose expansion, resulting in TAG mobilization from adipose to the liver and ultimately contributing to NAFLD/steatohepatitis. This inflammatory-driven axis also affects adipose responses to systemic metabolic change, sensitizing adipocytes to lipolytic regulation by other cAMP modulators. Finally, we present preliminary data that the IL-6 family of cytokines signal through JAK/STAT3 inducing the expression of adenylyl cyclase 5 (ADCY5) to reprogram adipocytes in regulating lipid mobilization. SA1 will evaluate the contribution of the LIFR-α/JAK/STAT3 signaling cascade in adipocytes to the Cytokine-Adipose-Hepatic Axis. SA2 will use a genetics-based approach to verify that cytokine-mediated reprogramming of adipocytes in promoting lipid mobilization requires ADCY5 function. SA3 will use single cell RNA-Seq techniques in our multiple mouse models to identify non-adipocyte contributors to inflammation-regulated obesity and NAFLD.


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 = $517,066 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/14/2025	NON-COMPETING CONTINUATION	$51,706
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/20/2025	NON-COMPETING CONTINUATION	$465,360
														Subtotal = $517,066

Issue Date FY: 2024 ( Subtotal = $496,510 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/6/2024	NON-COMPETING CONTINUATION	$31,030
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/22/2023	NON-COMPETING CONTINUATION	$465,480
														Subtotal = $496,510

Issue Date FY: 2023 ( Subtotal = $517,284 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/22/2022	NON-COMPETING CONTINUATION	$465,556
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/31/2023	NON-COMPETING CONTINUATION	$51,728
														Subtotal = $517,284

Issue Date FY: 2022 ( Subtotal = $517,286 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/27/2021	NEW	$517,286
														Subtotal = $517,286

Grand Total All Awards = $2,048,146

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LIFR-alpha/JAK/STAT3-dependent Adipose Inflammation Contributes to Obesity-Associated NAFLD - Resubmissi

Award Number: R01DK128166

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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