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Maternal Obesity Programs Offspring Hypothalamic Neurogenesis and Appetite: Mechanisms and Prevention of Hyperphagia-mediated Childhood Obesity

Award Number: R01HD099813
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/14/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Maternal Obesity Programs Offspring Hypothalamic Neurogenesis and Appetite: Mechanisms and Prevention of Hyperphagia-mediated Childhood Obesity - Abstract Throughout the US, Brazil and LMICs, obesity and metabolic syndrome are ongoing epidemic crises, presenting major public health challenges and significant economic burdens. The developmental programming effects of the in utero environment is demonstrated by the increased risk of childhood and adult obesity in offspring of overweight/obese (OW/OB) mothers. A murine model of maternal OB has been established in the US and Brazil, with studies from collaborating laboratories demonstrating that maternal OB and high fat diet results in offspring hyperphagia and obesity, similar to human programming effects. Based on published and preliminary studies in the US and Brazil, maternal OB “programs” the offspring putative appetite center, the arcuate nucleus (ARC). We propose that maternal OB induces neuroprogenitor cell (NPC) mitochondrial dysfunction, alters putative bHLH neurogenic signals and preferentially differentiates ARC to increased orexigenic (NPY/AgRP) vs anorexigenic (POMC) neurons, leading to hyperphagia and obesity. We propose to dissect the underlying molecular and epigenetic mechanisms by which fetal/neonatal nutrition alters hypothalamic neurogenesis, using complementary in vivo and in vitro studies, including Cre- recombinase mice, in order to identify targets for prevention/intervention. We will initiate studies of infant breast milk and formula intake, breast milk composition, and a novel preventative strategy of titrated infant weight gain to break the cycle of maternal-offspring OW/OB. The goals of this project are (i) combine Brazilian expertise on functional characterization of OB offspring with US expertise and experimental strategies on NPC culture, mitochondrial function and NPC stereotaxic transplantation, (ii) dissect the role of each candidate pathway in the neurogenic programming paradigm in vivo and in vitro, (iii) test an innovative, highly applicable intervention to prevent early life obesity, and (iv) expand the scientific, training and technical capabilities of Brazilian basic science and clinical research. Together, we will utilize in vivo and in vitro models to explore the pathway by which oxidative stress alters hypothalamic neurogenesis, and examine a novel strategy for prevention of programmed hyperphagia. This project will foster local and US training of Brazilian students and investigators in advanced techniques for brain studies, enhance and approaches to optimize infant feeding, stimulate nationwide public health awareness for the prevention of pre-conception and infant obesity, and build collegial networks between US and Brazil research communities to comprehensively tackle the problem of 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 = -$175,320 )
2026	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	11/24/2025	NON-COMPETING CONTINUATION	-$139,325
2026	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	4	12/29/2025	NON-COMPETING CONTINUATION	-$35,994
														Subtotal = -$175,320

Issue Date FY: 2023 ( Subtotal = $515,752 )
2023	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	5/12/2023	NON-COMPETING CONTINUATION	$515,752
														Subtotal = $515,752

Issue Date FY: 2022 ( Subtotal = $517,655 )
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	3	6/25/2022	NON-COMPETING CONTINUATION	$517,655
														Subtotal = $517,655

Issue Date FY: 2021 ( Subtotal = $517,295 )
2021	2021	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	5/17/2021	NON-COMPETING CONTINUATION	$517,295
2021	2020	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	1	6/1/2021	NEW	$0
														Subtotal = $517,295

Issue Date FY: 2020 ( Subtotal = $571,053 )
2020	2020	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	1	9/14/2020	NEW	$571,053
														Subtotal = $571,053

Grand Total All Awards = $1,946,436

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Maternal Obesity Programs Offspring Hypothalamic Neurogenesis and Appetite: Mechanisms and Prevention of Hyperphagia-mediated Childhood Obesity

Award Number: R01HD099813

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/14/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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