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miR-27 mediated regulation of mitochondrial function in thermogenic adipocytes

Award Number: R01DK124261
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: 09/16/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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miR-27 mediated regulation of mitochondrial function in thermogenic adipocytes - Project Summary/Abstract The obesity epidemic is a global public health issue, that leads to an increased risk for type 2 diabetes and cardiovascular disease. Hypertrophy, inflammation, and excess lipid accumulation in white adipocytes within fat tissue are hallmarks of obesity that contribute to metabolic dysfunction. Unlike white adipocytes, beige adipocytes are rich in mitochondria, and expend energy to generate heat (thermogenesis) in response to stimuli such as cold exposure. This activity is associated with resistance to diet-induced obesity, and thus activation and expansion of beige adipocytes can counteract the obesity phenotype. During beige adipocyte activation, optimal thermogenic function is maintained by balancing mitochondrial biogenesis with autophagy- mediated mitochondrial degradation (mitophagy), which is finely coordinated to maintain mitochondrial homeostasis. Using our newly developed model of beige adipocyte differentiation and activation from human iPS cells, we discovered that thermogenic activation of beige adipocytes occurs following enhanced secretion of exosomes containing a variety of microRNAs (miRs), including miR-27a/b. miR-27 homologs (miR-27a/b) are anti-thermogenic miRs that suppress genes involved in mitochondrial biogenesis (such as FOXJ3) and mitophagy (including MFF). miR-27a/b are down-regulated in beige adipocytes during thermogenic activation, consistent with their predicted role as inhibitors of mitochondrial activation, turnover, and biogenesis. This project tests several hypotheses related to mechanisms of beige adipocyte activation. We propose that the miR-27 suppresses adipocyte thermogenesis by targeting FOXJ3 and MFF and that loss of miR-27a/b and increase in FOXJ3/MFF-mediated pathways activate mitochondrial activity and thermogenesis. We also propose that in vivo genetic targeting of miR-27a/b will allow us to identify the in vivo role of these miRs in beige adipocyte activation, regulation of mitochondrial proteins, thermogenesis and resistance to obesity. These questions will be tested in two focused specific aims: Specific Aim 1. Identify the mechanism of miR-27 regulation of beige adipocyte mitochondrial function. Specific Aim 2. Determine the effect of miR-27 suppression on the response of beige adipose tissue to temperature challenge and high-fat diet. These studies are expected to identify novel molecular mechanisms that may provide a new platform to increase beige adipogenesis and reverse obesity-related 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 = $430,000 )
2025	2025	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/7/2025	NON-COMPETING CONTINUATION	$430,000
														Subtotal = $430,000

Issue Date FY: 2024 ( Subtotal = $412,800 )
2024	2024	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/9/2024	NON-COMPETING CONTINUATION	$412,800
														Subtotal = $412,800

Issue Date FY: 2023 ( Subtotal = $430,000 )
2023	2023	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/23/2023	NON-COMPETING CONTINUATION	$430,000
														Subtotal = $430,000

Issue Date FY: 2022 ( Subtotal = $430,000 )
2022	2022	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/27/2022	NON-COMPETING CONTINUATION	$430,000
														Subtotal = $430,000

Issue Date FY: 2021 ( Subtotal = $430,000 )
2021	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/16/2021	NEW	$430,000
														Subtotal = $430,000

Grand Total All Awards = $2,132,800

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miR-27 mediated regulation of mitochondrial function in thermogenic adipocytes

Award Number: R01DK124261

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: 09/16/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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