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Paracrine effects of leptin in regulating visceral fat expansion

Award Number: R01DK138035
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: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Paracrine effects of leptin in regulating visceral fat expansion - Project summary: Visceral adiposity is a major risk factor for the development of metabolic syndrome. A better understanding of visceral fat expansion in the progression of obesity may provide new strategies to treat obesity and its associated metabolic disorders. Visceral fat expansion requires the dedicated coordination between mature adipocytes and precursor cells. Recent advances using single cell sequencing have revealed the heterogeneity of visceral fat depots and identified two major precursor populations in PDGFRb+ stromal cells – adipogenic progenitor cells (APCs) and fibro- inflammatory progenitors (FIPs) – which contribute to visceral fat expansion during obesity. However, the main regulators that determine the fate of these two populations are largely unknown. Recently, we found that gene expression of leptin (lep) in visceral fat is much higher than it is in subcutaneous and brown fat. In response to acute high-fat diet (HFD) exposure (1 day), we found a rapid increase in lep gene expression in visceral fat depots, but not in subcutaneous and brown fat depots. This increase in lep gene expression in visceral fat is paired with a rapid expansion of APCs and FIPs, suggesting a regulatory role for leptin. In addition, during the progression to obesity, high leptin derived from visceral adipocytes creates a unique “hyperleptinemia” micro-environment, which promotes the expansion of FIPs and leads to adipose tissue hypertrophy and inflammation. Therefore, we hypothesize that leptin from visceral fat is a significant regulatory element of the detrimental effects of visceral adiposity and controls visceral fat expansion by regulating precursor cells-FIPs and APCs. In this proposal, we will take advantage of novel and well-established mouse models, paired with biochemical techniques to uncover the paracrine effects of leptin in the regulation of visceral fat expansion, with three specific Aims: Aim 1 is to determine whether visceral- derived leptin contributes to the detrimental effects of visceral adiposity; Aim 2 is to assess the paracrine effects of leptin in regulating the fate of FIPs and APCs; Aim 3 is to investigate the effect of CXCL14 in mediating visceral fat healthy expansion. Combined, these studies will provide new insights into paracrine effects of leptin in regulating the fate of FIPs and APCs, leading to an unhealthy visceral fat expansion and developing visceral adiposity. In addition, this study will offer an entirely novel means to combat against visceral adiposity by targeting on leptin/CXCL14 axis.


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 = $387,500 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/25/2026	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2025 ( Subtotal = $387,500 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/13/2025	NON-COMPETING CONTINUATION	$38,750
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/27/2025	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $387,500

Issue Date FY: 2024 ( Subtotal = $387,500 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/15/2024	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $1,162,500

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Paracrine effects of leptin in regulating visceral fat expansion

Award Number: R01DK138035

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: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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