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Paternal Contributions to Metabolic Disease in Offspring: Environment, Epigenetics, and Sperm

Award Number: R01DK106193
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY One novel approach to reduce the burden of type 2 diabetes and obesity comes from the recognition that parental obesity or diabetes can increase risk of metabolic disease in offspring via non-genetic effects. This perspective raises the exciting possibility that treatment of parents to improve their metabolism before conception could interrupt vicious intergenerational cycles of obesity and diabetes, thus improving offspring health. In the prior funding cycle, we developed evidence for the impact of paternally-focused interventions on the sperm epigenome and offspring health. We recently demonstrated in humans that paternal obesity is associated with altered DNA methylation in cord blood of offspring7. Our new data in mice indicate (1) paternal obesity and hyperglycemia are key determinants of offspring health, (2) improving paternal metabolism - by treatment with either SGLT2 inhibitors or caloric restriction - can reverse age-associated weight gain, insulin resistance, glucose intolerance, and fatty liver in F1 offspring, (3) paternal metabolism potently modifies the transcriptome in fetal and adult offspring, including oxidative and lipid regulatory genes, and (4) paternal metabolism alters the epigenome in both sperm and offspring tissue. For example, DNA hydroxymethylation (5hmC) at enhancers adjacent to differentially expressed genes is reduced in sperm of HFD-fed males, and reciprocally increased in males treated with SGLT2i or the AMP kinase activator AICAR. In this revised application, we will utilize this innovative mouse model to identify the mechanisms by which paternal health and its treatment modulate the paternal germ cell epigenome to improve offspring health, and to test the hypothesis that the AMPK-Tet2 pathway, a mediator of glucose-mediated epigenetic regulation, mediates observed differences in sperm 5hmC and offspring metabolic disease. In Aim 1, we will define the impact of paternal obesity and hyperglycemia, and its reversal, on the germ cell epigenome (5mC/5hmC, small RNA), and identify key cis-regulating elements. In Aim 2, we will determine the pathogenicity of germ cell epigenetic changes by evaluating offspring outcomes after in vitro fertilization and sperm-derived ncRNA injection. Aim 3 will determine whether paternal effects on offspring are mediated via direct effects on the embryo, or on extraembryonic lineages affecting placental development, using single-cell transcriptomic analysis of blastocysts at a single-cell level and detailed morphometric analysis of placentae derived from control, HFD, and HFD+CANA-treated fathers. Aim 4 will test the hypothesis that the AMPK-Tet2 pathway, a mediator of glucose- mediated epigenetic regulation in somatic cells, also mediates glucose-induced changes in the germ cell epigenome. We will analyze the impact of AMPK activation in vivo on 5hmC in sperm from wild type or Tet2-null mice and on offspring phenotypes. In summary, identification of causal mechanisms in response to paternal hyperglycemia and obesity - and its reversal - will provide critical new information to guide development of new paternally-focused translatable approaches to reduce disease burden in future generations.


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: 2023 ( Subtotal = $733,550 )
2023	2023	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	5/29/2023	NON-COMPETING CONTINUATION	$733,550
														Subtotal = $733,550

Issue Date FY: 2022 ( Subtotal = $741,030 )
2022	2022	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/1/2022	NON-COMPETING CONTINUATION	$741,030
														Subtotal = $741,030

Issue Date FY: 2021 ( Subtotal = $801,134 )
2021	2021	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	9/3/2021	COMPETING CONTINUATION	$801,134
2021	2019	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $801,134

Issue Date FY: 2019 ( Subtotal = $318,539 )
2019	2019	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/12/2019	NON-COMPETING CONTINUATION	$318,539
														Subtotal = $318,539

Issue Date FY: 2018 ( Subtotal = $323,718 )
2018	2018	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/26/2018	NON-COMPETING CONTINUATION	$32,372
2018	2018	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/1/2018	NON-COMPETING CONTINUATION	$291,346
														Subtotal = $323,718

Issue Date FY: 2017 ( Subtotal = $323,718 )
2017	2017	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/13/2017	NON-COMPETING CONTINUATION	$32,372
2017	2017	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/14/2017	NON-COMPETING CONTINUATION	$291,346
														Subtotal = $323,718

Issue Date FY: 2016 ( Subtotal = $342,484 )
2016	2016	JOSLIN DIABETES CENTER, INC	ONE JOSLIN PLACE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/1/2016	NEW	$342,484
														Subtotal = $342,484

Grand Total All Awards = $3,584,173

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Paternal Contributions to Metabolic Disease in Offspring: Environment, Epigenetics, and Sperm

Award Number: R01DK106193

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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