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Deciphering age-dependent beige adipocyte failure

Award Number: R01DK132264
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: 03/15/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Deciphering age-dependent beige adipocyte failure - PROJECT SUMMARY: Cold temperature (<15°C) exposure stimulates perivascular beige adipocyte progenitor cells (bAPCs) to generate beige adipocytes. Beige adipocytes act as cellular furnaces to burn blood glucose and free fatty acids to generate heat. Recent studies have shown the metabolic benefits of beige adipocytes, suggesting potential clinical efficacy for obese patients and type 2 diabetics. However, the potential to form cold-induced beige adipocytes declines with age, creating a pivotal challenge to the therapeutic promise for older individuals, many of whom constitute the obesity epidemic. Our studies begin to unravel how aging suppresses beige adipogenic potential and identifies new ways to rejuvenate beige fat cell biogenesis to restore metabolic fitness in aged mammals. Our previous studies have linked cellular senescence, a state of cellular arrest, of bAPCs to the age- associated decline in beige adipose tissue. In an attempt to find additional mechanisms blocking beige fat biogenesis in aged mammals, we found that the expression and signaling of platelet derived growth factor receptor beta (Pdgfrβ) is increased in aged bAPCs. Moreover, ablation of Pdgfrβ within the beige adipose lineage restored beige adipocyte generation and improved metabolic health in aged (not young) mice. Despite beige fat formation in aged Pdgfrβ-deficient mice, lineage-tracing studies revealed that auxiliary source(s) generated beige adipocytes. In agreement, senescence tests demonstrated that Pdgfrβ neither promoted nor reversed cellular senescence. Instead, we found that Pdgfrβ signaling prevents group 2 innate lymphoid cell (ILC2) recruitment and activation within iWAT depots. Mechanistically, we identified that Pdgfrβ elicits signals via Stat1 to suppress the ILC2-inducer, interleukin-33 (IL-33), to control WAT ILC2 activity. Finally, we identify sympathetic tone as a significant regulator of age-induced Pdgfrβ expression. Our aims will elucidate the physiological and cellular role of Pdgfrβ in regulating beige fat biogenesis under aging and obese conditions. We will elucidate the Pdgfrβ-Stat1 signaling mechanism in bAPCs to control ILC2 recruitment via IL-33. We uncover how sympathetic output regulates Pdgfrβ expression to drive the age-dependent beige adipogenic failure. These findings will implicate Pdgfrβ signaling as a central node in the bAPC aging process. Importantly, this application will identify factors that reverse age-dependent beige adipogenic failure with a direct clinical utility to combat excess body fat and metabolic dysfunction to extend lifespan and restore health.


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 = $448,009 )
2026	2026	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/28/2026	NON-COMPETING CONTINUATION	$448,009
														Subtotal = $448,009

Issue Date FY: 2025 ( Subtotal = $432,536 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/25/2025	NON-COMPETING CONTINUATION	$432,536
														Subtotal = $432,536

Issue Date FY: 2024 ( Subtotal = $417,767 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/20/2024	NON-COMPETING CONTINUATION	$26,108
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/30/2024	NON-COMPETING CONTINUATION	$391,659
														Subtotal = $417,767

Issue Date FY: 2023 ( Subtotal = $423,660 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$423,660
														Subtotal = $423,660

Issue Date FY: 2022 ( Subtotal = $408,816 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/10/2022	NEW	$408,816
														Subtotal = $408,816

Grand Total All Awards = $2,130,788

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Deciphering age-dependent beige adipocyte failure

Award Number: R01DK132264

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: 03/15/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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