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A leptin-responsive lateral hypothalamus to ventrolateral periaqueductal gray circuit for palatable food overconsumption

Award Number: R01DK132566
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: 04/07/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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A leptin-responsive lateral hypothalamus to ventrolateral periaqueductal gray circuit for palatable food overconsumption - PROJECT SUMMARY/ABSTRACT Obesity is a global public health crisis, and its prevalence continued to increase dramatically during the last three decades. Although numerous factors influence on body weight, excessive consumption of palatable foods (e.g., high-fat diet, HFD) is a major risk factor leading to obesity. Notably, most of the individuals who achieved a successful diet with withdrawal from such foods show high rates of relapse to HFD overconsumption. Given that this process is highly associated with the increased preference for palatable foods, understanding neural circuit mechanisms leading to HFD overconsumption after abstinence is arguably the core issue in therapeutic strategies for the long-term treatment of obesity. However, neither the specific neural circuit pathway nor the molecular mechanisms underlying this process are well understood. Leptin, an adipose tissue-derived hormone, exerts its anorexic effects by acting on its receptors in the hypothalamus. Activation of long leptin receptor (LepR) stimulates multiple signal transduction pathways to suppress food intake and weight gain. While a decrease in hypothalamic tissue sensitivity to leptin is characterized by a disturbance in the ability of LepR to activate downstream effectors or impairment in LepR expression, we do not understand critical issues concerning primary brain circuit that develops leptin insensitivity which can subserve relapse to HFD overconsumption. Thus, in this proposal we aim to propose an interdisciplinary approach to understand the circuit-specific role of leptin sensitivity in driving HFD overconsumption following abstinence from such foods. We will primarily focus on the leptin-responsive circuit that connects the lateral hypothalamus (LH) to the ventrolateral periaqueductal gray (vlPAG) and functionally probe its neural adaptation after HFD exposure. The central objective of this proposal is to determine the neural dysfunction of LepR-expressing LH (LepR LH) neurons projecting to the vlPAG using the intermittent access schedule of HFD to better understand the neural mechanisms underlying HFD overconsumption when the food becomes more salient. To achieve our objective, we will first characterize in vivo activity of target-specific LepR LH neurons during HFD consumption at different food stages. We will examine whether the vlPAG-projecting LepR LH neurons are engaged in post-abstinence HFD overconsumption (Aim 1). Secondly, using molecular profiling methods, we will examine how HFD abstinence induces circuit- specific neural adaptation in the LepR signaling associated with HFD overconsumption (Aim 2). Third, we will determine how LepR knockdown-induced leptin insensitivity in the LepR LH neurons regulates HFD consumption and body weight with a circuit-specific manner (Aim 3). The significance of this study is substantial because it represents the first steps towards understanding how leptin-responsive LH-vlPAG circuitry controls HFD consumption that is exacerbated by abstinence. The contribution is innovative because it will provide, for the first time, a framework for studying the circuit-specific role of leptin sensitivity in relapse to HFD overconsumption, and in developing targeted therapies for the treatment of pathological symptoms in eating disorders and obesity.


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 = $418,986 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/27/2026	NON-COMPETING CONTINUATION	$418,986
														Subtotal = $418,986

Issue Date FY: 2025 ( Subtotal = $418,403 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/28/2025	NON-COMPETING CONTINUATION	$418,403
														Subtotal = $418,403

Issue Date FY: 2024 ( Subtotal = $416,306 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/15/2024	NON-COMPETING CONTINUATION	$26,018
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/28/2024	NON-COMPETING CONTINUATION	$390,288
														Subtotal = $416,306

Issue Date FY: 2023 ( Subtotal = $414,243 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/28/2023	NON-COMPETING CONTINUATION	$414,243
														Subtotal = $414,243

Issue Date FY: 2022 ( Subtotal = $437,300 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/7/2022	NEW	$437,300
														Subtotal = $437,300

Grand Total All Awards = $2,105,238

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A leptin-responsive lateral hypothalamus to ventrolateral periaqueductal gray circuit for palatable food overconsumption

Award Number: R01DK132566

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: 04/07/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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