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Lateral Hypothalamic circuit dysfunction underlying the development of diet-induced obesity

Award Number: R01DK136641
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Lateral Hypothalamic circuit dysfunction underlying the development of diet-induced obesity - Project Summary The brain is a critical mediator of energy homeostasis, and neurocircuit dysfunction is thought to underlie obesity pathogenesis. Within the brain, the lateral hypothalamic area (LHA) exerts control over feeding behavior and body weight. Because of its considerable molecular and functional complexity, the role of LHA neurons in the development of diet-induced obesity (DIO) is still poorly understood. Addressing the LHA mechanisms governing feeding behavior and how they are remodeled during DIO will help to develop more targeted therapeutic interventions for obesity. Our overarching goal is to gain a mechanistic understanding of LHA neuronal dysfunction in DIO. Our previous work has demonstrated that the two most abundant cell types in the LHA— glutamatergic (LHAGlut) and GABAergic (LHAGABA) neurons—are transcriptionally remodeled by DIO. LHAGlut and LHAGABA neurons functionally oppose one another: LHAGlut neurons suppress feeding and reduce body weight, whereas LHAGABA neurons promote feeding and increase body weight. Our preliminary data confirm that LHAGlut and LHAGABA neurons show opposing changes in activity during acute manipulations of energy state and exhibit opponent transcriptional changes during DIO. These results highlight a potential role for LHA neuron dysfunction as a cause for overeating and DIO. However, the mechanisms underlying LHAGlut and LHAGABA neuron dysfunction in DIO are unknown. One factor that influences energy homeostasis, feeding behavior, and LHA activity is glucose. We therefore hypothesize that alterations in responsivity to glucose contribute to LHAGlut and LHAGABA neuron dysfunction in acute and chronic overnutrition and that restoration of LHA neuron activity can reverse the metabolic and behavioral impairments observed in DIO. To test this, we will determine the temporal dynamics of LHAGlut and LHAGABA neuron remodeling in DIO using longitudinal multiphoton in vivo imaging and electrophysiology. We will then test the hypothesis that glucose changes the activity of LHAGlut and LHAGABA neurons in vivo after acute and chronic overfeeding. Finally, we will test the hypothesis that restoration of LHAGlut and LHAGABA neuron activity can reverse the adverse consequences of chronic overnutrition. The results of this project will advance our conceptual understanding of the brain's involvement in DIO and identify novel therapeutic targets for the treatment of 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: 2025 ( Subtotal = $437,700 )
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	3	6/30/2025	NON-COMPETING CONTINUATION	$437,700
														Subtotal = $437,700

Issue Date FY: 2024 ( Subtotal = $423,471 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/14/2024	NON-COMPETING CONTINUATION	$423,471
														Subtotal = $423,471

Issue Date FY: 2023 ( Subtotal = $434,969 )
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	8/30/2023	NEW	$434,969
														Subtotal = $434,969

Grand Total All Awards = $1,296,140

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Lateral Hypothalamic circuit dysfunction underlying the development of diet-induced obesity

Award Number: R01DK136641

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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