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Adipose tissue mediates cardiac metabolic remodeling in the pathologically stressed heart in the absence of primary metabolic stress

Award Number: R01HL164290
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Adipose tissue mediates cardiac metabolic remodeling in the pathologically stressed heart in the absence of primary metabolic stress - Project Summary: The pathogenesis of heart failure is linked to systemic metabolic dysfunction, a comorbidity likely involving peripheral organs, and resulting in insulin resistance in patients with and without diabetes. This study focuses on the reciprocal response of adipose tissue to pathological stress on the heart and will investigate how adipose tissue activity affects cardiac metabolic remodeling. This proposal originates from novel findings by each of the MPI laboratories. We have identified transient changes in adipose tissue plasticity during the pathogenesis of decompensated cardiac hypertrophy in response to pathological stress alone, absent any primary metabolic stress, such as diabetes, nutrient overload, or obesity. This finding and our unpublished data implicate cardiac natriuretic peptides (NP) as mediators of adipose activation and show that NPs are induced by a reduction in long chain fatty acid (LCFA) oxidation by the heart, even without pathological stress. Preliminary data reveal a profound, sex-specific array of early responses in white (WAT) and brown (BAT) adipose tissue activity to cardiac pressure overload that include beiging of WAT and induction of a lipolytic phenotype with cold exposure. While the cardiac responses to pathological stress include maladaptive remodeling of lipid metabolism, the effects of adipose plasticity on the cardiac lipid profile during the development of pathological hypertrophy are virtually unexplored. Thus, we hypothesize that: 1) the metabolic response of reduced fatty acid oxidation in the heart during pathological stress induces plasticity of WAT that is mediated by cardiac NPs in a sex-specific manner, distinct from β-adrenergic stimulation, with downstream effects on glucose tolerance; and 2) sustained beiging of WAT and activation of BAT confer cardioprotection against adverse cardiac metabolic remodeling. The research design supports three specific aims: 1. Elucidate effects of adipocyte adrenergic activation on WAT beiging, and responses of cardiac LCFA metabolism during TAC with adipose adrenergic activation and inhibition; 2. Determine whether adipose plasticity results from NP effects in direct response to TAC or from the metabolic shift of reduced LCFA oxidation in male and female mice; 3. Investigate a potential cardioprotective role of adipose browning on the lipid profile of failing hearts. The overall objectives are to: 1) determine the reciprocal metabolic responses between the pathologically stressed heart and adipose tissue via cardiac NP production and adipokine/lipokine release (namely 12,13-diHOME), respectively; 2) elucidate the consequences of sex differences in the responses of adipose tissue and myocardium to cardiac stress; and 3) explore the potential for WAT beiging or BAT activation to provide cardioprotection via metabolic signaling. The findings will contribute new insights into the adipose responses and contributions to metabolic remodeling of the heart during the pathogenesis of decompensated cardiac hypertrophy, with the potential to identify targets for remediating the progression to overt heart failure and improving peripheral and systemic metabolic dysfunction.


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: 2026 ( Subtotal = $769,850 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	4	4/7/2026	NON-COMPETING CONTINUATION	$769,850
														Subtotal = $769,850

Issue Date FY: 2025 ( Subtotal = $785,561 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	3	7/16/2025	NON-COMPETING CONTINUATION	$78,556
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	3	3/5/2025	NON-COMPETING CONTINUATION	$707,005
														Subtotal = $785,561

Issue Date FY: 2024 ( Subtotal = $769,850 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	2	6/22/2024	NON-COMPETING CONTINUATION	$62,845
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	2	3/5/2024	NON-COMPETING CONTINUATION	$707,005
														Subtotal = $769,850

Issue Date FY: 2023 ( Subtotal = $785,561 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	3/15/2023	NEW	$785,561
														Subtotal = $785,561

Grand Total All Awards = $3,110,822

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Adipose tissue mediates cardiac metabolic remodeling in the pathologically stressed heart in the absence of primary metabolic stress

Award Number: R01HL164290

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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