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Hepatic fat accumulation in nonalcoholic fatty liver disease: critical regulation by kisspeptin signaling

Award Number: R01DK129870
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: 04/30/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Hepatic fat accumulation in nonalcoholic fatty liver disease: critical regulation by kisspeptin signaling - Obesity, a long-standing pandemic in the United States, is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common chronic liver disease globally, affecting about one third of adults, for which there is no approved medication. The first stage of NAFLD is steatosis (fatty liver), a condition that can progress to non-alcoholic steatohepatitis (NASH) where fat accumulation in the liver is associated with inflammation, fibrosis and scarring, resulting in the eventual loss of liver function. There is therefore a dire need to understand the molecular mechanisms underlying the development of fatty liver and NASH to create the first identified targets for medication. The liver produces a peptide known as kisspeptin (KP), that signals by binding a G protein-coupled receptor, the kisspeptin 1 receptor (KISS1R) expressed in the liver. The metabolic functions of KISS1R signaling in the liver, however, are not known. We found that hepatic KP/KISS1R expression are upregulated in high fat diet induced mouse model of NAFLD. We also observed that when mice lacking hepatic KISS1R were challenged with high fat diet-feeding, they showed increased hepatic steatosis, insulin resistance, and an upregulation of inflammatory and fibrosis markers, compared to controls on the same diet. Taken together, this data led us to hypothesize that hepatic KISS1R activation suppresses hepatic lipogenesis thus limiting fat accumulation and NASH development. The proposed work will decipher the mechanisms by which KISS1R signaling inhibits fatty liver and NASH. In Aim 1, we will investigate the mechanisms by which hepatic KISS1R signaling modulates hepatic lipid levels by inhibiting lipogenesis. In Aim 2, we will assess the impact of enhancing KISS1R signaling on the development of NAFLD. In Aim 3, we will study the clinical relevance of KP/KISS1R signaling pathway by measuring plasma KP levels in healthy subjects, NAFLD and NASH patients and assess whether plasma KP levels correlate with metabolic disease severity and other anthropometric, laboratory, radiographic and demographic features. Additionally, the expression and localization of hepatic KISS1R in NAFLD/NASH liver biopsies will be examined. Understanding this knowledge is important because it will shed light on using the KISS1R signaling pathway as a potential avenue to develop a novel pharmacological approach to reduce NAFLD and NASH.


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 = $0 )
2026	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/14/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $473,236 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/17/2025	NON-COMPETING CONTINUATION	$473,236
														Subtotal = $473,236

Issue Date FY: 2024 ( Subtotal = $458,598 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	5/3/2024	NON-COMPETING CONTINUATION	$458,598
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	12/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$185,928
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	12/19/2023	NEW	-$185,928
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/19/2023	NEW	$0
														Subtotal = $458,598

Issue Date FY: 2023 ( Subtotal = $477,015 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$477,015
														Subtotal = $477,015

Issue Date FY: 2022 ( Subtotal = $515,309 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/22/2022	NEW	$515,309
														Subtotal = $515,309

Grand Total All Awards = $1,924,158

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Hepatic fat accumulation in nonalcoholic fatty liver disease: critical regulation by kisspeptin signaling

Award Number: R01DK129870

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: 04/30/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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