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Activation of C/EBP-β by mitohormesis as a therapy for obesity

Award Number: K01DK128128
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Activation of C/EBP-β by mitohormesis as a therapy for obesity - Project Summary It is estimated that around 40% of the adult population of the United States is obese and thus at increased risk for several chronic illnesses. Current weight loss strategies for obese people are often ineffective and come with serious neurological side effects. This proposal aims to determine whether new strategies to treat and prevent obesity can be developed from current insights into biological aging. The transcription factor C/EBP-β regulates the expression of genes involved in fat catabolism and fat stores mobilization. Preliminary observations suggest that pro-longevity interventions, such as mTORC1 inhibition, prevent diet-induced obesity in mice and activate C/EBP-β. The nucleoside-analogue reverse-transcriptase inhibitor (NRTI) adefovir dipivoxil (ADV) also prevents diet-induced obesity and activates C/EBP-β, though independently of mTORC1 inhibition. Building on these premises, Aim 1 tests the hypothesis that activation of hepatic C/EBP-β leads to increased energy expenditure and fat catabolism, with net negative effects on weight and fat stores. Using transgenics and pharmacological approaches, we will determine the role of hepatic C/EBP-β in lipid metabolism and homeostasis in the face of obesogenic challenges and morbid obesity. State-of-the-art techniques will be applied to measure the impact of different isoforms of C/EBP-β on energy balance, glucose homeostasis, and endocrine regulation of glucose and lipid metabolism. Aim 2 sets out to determine whether mitohormetic stresses can increase lipid metabolism through activation of C/EBP-β. Using ADV and other mitochondrial stressors, we will measure activation of mitohormetic pathways and their connection with increased hepatic oxidation of fatty acids and energy expenditure. This proposal will be carried out in an institution with strong research programs in both aging and obesity/diabetes biology. The candidate will receive state of the art training in techniques and analytical tools necessary to the completion of both aims, including indirect calorimetry, insulin and glucose tolerance testing, and big data analysis. The candidate will also acquire an in-depth background in energy and nutrient homeostasis. Altogether, the experiments and training proposed will allow the candidate to build an independent and successful research program applying insights from geroscience to understand and investigate nutrient homeostasis, energy balance, and related metabolic disorders.


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 = $146,750 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/17/2025	NON-COMPETING CONTINUATION	$146,750
														Subtotal = $146,750

Issue Date FY: 2024 ( Subtotal = $146,750 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/19/2024	NON-COMPETING CONTINUATION	$146,750
														Subtotal = $146,750

Issue Date FY: 2023 ( Subtotal = $146,750 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/19/2023	NON-COMPETING CONTINUATION	$146,750
														Subtotal = $146,750

Issue Date FY: 2022 ( Subtotal = $148,251 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/17/2022	NEW	$148,251
														Subtotal = $148,251

Grand Total All Awards = $588,501

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Activation of C/EBP-β by mitohormesis as a therapy for obesity

Award Number: K01DK128128

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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