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Sex Differences in Postprandial Lipid Metabolism

Award Number: R01DK128898
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: 07/20/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Sex Differences in Postprandial Lipid Metabolism - The high levels of saturated fat in Western diets contribute to the risk for obesity, diabetes and cardiovascular disease. Consumption of a fat-rich mean triggers a surge in circulating triglyceride TG levels as well as an inflammatory response that last several hours. As a result, we may spend a majority of our waking hours in a postprandial state. Non-fasting/postprandial TG levels are an independent predictor for cardiovascular disease. Studies in humans of multiple ethnic groups, as well as in the mouse, indicate that biological sex is a key determinant of postprandial hyperlipidemia, with males experiencing higher postprandial TG levels and inflammatory response. Knowledge gaps remain in our understanding of the physiological and molecular processes that differ between males and females to influence postprandial lipid handling and inflammation. Furthermore, the components of biological sex (which include ovarian and testicular hormones as well as genetic sex determinants, the XX and XY sex chromosomes) have not been systematically investigated with respect to postprandial metabolism. Our preliminary studies indicate that a lipid meal leads to substantially higher and more persistent circulating TG levels in males compared to females regardless of time of meal administration (i.e., during a typical fasting or feeding period) or presence of gut microbiota (the sex difference persists in gnotobiotic mice). Male mice also experience an enhanced postprandial inflammatory response, characterized by increased circulating monocyte number and inflammatory gene expression in bone marrow cells. Preliminary mechanistic studies indicate that rates of postprandial lipoprotein appearance in the circulation are similar in males and females, but that lipid composition and lipolysis differ. Our studies in the Four Core Genotypes mouse model reveal that the sex difference in postprandial hypertriglyceridemia is associated with gonadal sex (levels correlate with presence of ovaries vs. testes), whereas postprandial LPS levels are associated with sex chromosomes (presence of XX vs. XY). We propose to identify physiological and sex-related mechanisms that drive differences in postprandial lipid metabolism between males and females. Aim 1: Identify the metabolic processes and bioactive lipid components that promote male-biased postprandial hypertriglyceridemia and inflammation. We will perform in vivo and ex vivo studies in male and female mice to identify the mechanisms that lead to sex-biases in postprandial lipid composition, lipolysis, and inflammatory activation. Aim 2: Elucidate the control of postprandial lipid metabolism and inflammation by gonadal sex and chromosomal sex. Our studies in Four Core Genotypes mice revealed that distinct sex components influence postprandial lipid levels and inflammation. We will test the hypotheses that estradiol and/or testosterone regulate postprandial TG levels (using gonadectomized mice and hormone replacement), whereas the sex chromosome complement is a determinant of postprandial endotoxemia and inflammatory responses (using the XY* mouse model to compare animals with XX, XY, XO and XXY chromosome complements).


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: 2024 ( Subtotal = $431,362 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/23/2024	NON-COMPETING CONTINUATION	$431,362
														Subtotal = $431,362

Issue Date FY: 2023 ( Subtotal = $449,336 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/23/2023	NON-COMPETING CONTINUATION	$449,336
														Subtotal = $449,336

Issue Date FY: 2022 ( Subtotal = $449,336 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/18/2022	NEW	$449,336
														Subtotal = $449,336

Grand Total All Awards = $1,330,034

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Sex Differences in Postprandial Lipid Metabolism

Award Number: R01DK128898

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: 07/20/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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