Wednesday, October 1, 2025 10/1/2025

Hypothalamic regulation by thyroid hormone receptor phosphorylation

Award Number: R01DK136661
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: 12/08/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2027

Group Awards By:

View Award Description

Hypothalamic regulation by thyroid hormone receptor phosphorylation - Three major thyroid hormone receptor (THR) isoforms, expressed from two genetic loci (Thra and Thrb), are present in mammals: THRA1, THRB1, and THRB2. Thyroid hormone (TH) acting through THRs regulate food intake metabolism and the hypothalamic-pituitary-thyroid (HPT) axis in man. Our laboratories have long been interested in the THRB2 isoform as a central regulator of the hypothalamic-pituitary-thyroid (HPT) axis, given its unique and limited-expression pattern. We recently found that THRB2 is heavily phosphorylated by both TH and AMP kinase (AMPK) at an N-terminal serine site (S101-mouse, S102-human), not found in other THRs. Based on increased food intake, obesity, and TH resistance in mice carrying a mutation of this phosphorylation site (S101A), we hypothesize that an AMPK-dependent THRB2 S101 phosphorylation pathway in the hypothalamus suppresses food intake and the HPT axis. We also hypothesize that dysfunction of this pathway results in leptin resistance, increased food intake, and obesity (Fig. 1). Three closely related aims are proposed: Specific Aim 1: Functionally co-localize hypothalamic THRB2 and AMPK action on feeding. Both the arcuate (ARC) and ventromedial nucleus (VMN) regulate feeding in a THRB- and AMPK-dependent manner. To begin to functionally localize THRB2 action in the hypothalamus, THRB2 will be removed from the POMC neurons in the ARC and SF-1 neurons in the VMN using Thrb2 floxed mice and cell-specific Cre drivers. Cell- specific KO of AMPKa2 in the same neurons will also be performed to understand AMPKa2’s role in feeding and in the p-THRB2 pathway. Both male and female mice will be studied, given higher THRB2 expression in female HA-tagged THRB2 mice. Specific Aim 2: Determine the role of THRB2 phosphorylation in feeding and mediating hypothalamic leptin signaling. Previous studies have clearly demonstrated that leptin regulates both the HPT axis and feeding. A potential mediator of leptin action is p-THRB2, given that S101A mice demonstrate leptin resistance. A phospho-specific antibody was developed to probe this pathway further and will be used in a time- course study of THRB2 phosphorylation during the fed-fasting transition. Furthermore, a phosphomimetic S101D KI mouse model was generated to determine if this change protects against diet-induced obesity. Specific Aim 3: Define the locus of TRH regulation by THRB2 during fasting. While fasting-induced suppression of the HPT axis is mediated by reduced TRH expression in the paraventricular nucleus (PVN), it remains unknown how HPT axis suppression is maintained in the setting of low TH levels. Strikingly, S101A mice display resistance to fasting-induced TRH suppression, suggesting that THRB2 S101 phosphorylation is critical in the sensing of low TH levels. This aim will determine the locus of fasting-induced and TH-dependent TRH suppression by targeting neurons in the ARC and PVN. The mechanism of suppression will be explored further by studying if THRB2 phosphorylation is a common mechanism regulating the HPT axis and food intake.


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: 2025 ( Subtotal = $624,390 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	6/30/2025	NON-COMPETING CONTINUATION	$624,390
2025	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2025	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/19/2025	NEW	-$1
														Subtotal = $624,390

Issue Date FY: 2024 ( Subtotal = $607,857 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	7/3/2024	NON-COMPETING CONTINUATION	$607,857
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	4/10/2024	NEW	-$656,544
2024	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$656,544
														Subtotal = $607,857

Issue Date FY: 2023 ( Subtotal = $656,545 )
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	1	8/16/2023	NEW	$656,545
														Subtotal = $656,545

Grand Total All Awards = $1,888,792

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Hypothalamic regulation by thyroid hormone receptor phosphorylation

Award Number: R01DK136661

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: 12/08/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer