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A cardiac Wingless-Snail-Tep2 axis directs normal lipid homeostasis and protects against diet-induced obesity

Award Number: R01HL152205
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract The heart is now recognized as an important organ in the regulation of systemic lipid homeostasis; however, our understanding of the molecular basis remains limited. It was recently shown that Wingless (Wg) signaling in the heart controls systemic lipid homeostasis. However, how cardiac Wg signaling controls this process is unknown. In a genetic screen in Drosophila, we discovered that the Snail family of transcription factors (Sna TFs) act in the heart to regulate systemic lipid metabolism. Our preliminary results also showed that Wg signaling in the heart activates the cardiac expression of Sna TFs. These findings led us to hypothesize that a Wg-Sna TF axis in the heart regulates lipid homeostasis in a systemic manner. This hypothesis will be tested in Aim 1. Building on our previous proteomic analysis of fly hemolymph (blood), we further discovered that a soluble protein thioester-containing protein 2 (Tep2), a secreted protein previously unknown to be involved in lipid metabolism, is up-regulated in the heart by Sna signaling and secreted to the circulation. Our further preliminary data showed that Tep2 mutation alters systemic lipid levels and that both Sna TF and Tep2 control TGF¿ signaling in the fat body, in which TGF¿ is known to be implicated in lipid metabolism. We therefore hypothesize that Tep2 secreted from heart to circulation serves as a functional effector of Wg-Sna axis in regulating systemic lipid homeostasis by modulating TGF¿ pathway in fat body. This hypothesis will be tested in Aim 2. Furthermore, we found that high fat diet (HFD) induces the cardiac expression of Wg and Sna TFs. Based on our preliminary observation that activation of Sna TFs decreases systemic lipid levels, we hypothesize that a cardiac Wg¿Sna TF–Tep2 axis protects against HFD-induced obesity. This hypothesis will be tested in Aim 3. Together, this proposal will reveal novel insights into the heart control of normal systemic lipid homeostasis and provide knowledge that may help guide future therapeutics for human obesity and its comorbidities.


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 = $362,500 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	5	3/11/2024	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2023 ( Subtotal = $362,500 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	4	3/13/2023	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2022 ( Subtotal = $362,500 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	001	3	6/29/2022	NON-COMPETING CONTINUATION	$36,250
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	3	3/10/2022	NON-COMPETING CONTINUATION	$326,250
														Subtotal = $362,500

Issue Date FY: 2021 ( Subtotal = $362,500 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	2	3/12/2021	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2020 ( Subtotal = $362,500 )
2020	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	1	3/22/2020	NEW	$362,500
														Subtotal = $362,500

Grand Total All Awards = $1,812,500

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A cardiac Wingless-Snail-Tep2 axis directs normal lipid homeostasis and protects against diet-induced obesity

Award Number: R01HL152205

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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