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CRISPR-enhanced adipocyte browning to improve glucose tolerance in obesity and diabetes

Award Number: R01DK130852
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: 09/17/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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CRISPR-enhanced adipocyte browning to improve glucose tolerance in obesity and diabetes - Abstract The long term goal of this project is to understand the mechanisms by which human “beige” adipocytes improve metabolic health. We leverage CRISPR-based technology that enables human white adipocytes to maintain a maximally “beige” thermogenic phenotype. These CRISPR-modified cells greatly enhance metabolic health when implanted into obese, diabetic mice, facilitating discovery of mechanisms involved as well as providing a pre-clinical model for potential cell-based therapies. The premise of this work is supported by our demonstration, during the previous funding period, that human and mouse beige adipocytes implanted into “humanized” mice develop beige adipose depots that cause improved glucose tolerance and insulin sensitivity, with loss of body weight and decreased liver steatosis (1,2). These results can explain the remarkably strong correlation between the abundance (3-5) and activities (6-8) of beige adipose tissue and cardiometabolic health in humans. The CRISPR-based Nrip1 gene disruption method we developed to cause “beiging” of human adipocytes does not require viral or expression vectors, but instead delivers purified, endotoxin-free Cas9 protein and sgRNA complexes to human adipocyte progenitors with nearly 100 percent knockout efficiency. The key question now is: what are the mechanisms by which human beige adipose depots mediate beneficial systemic metabolic effects? We hope to crack this question by focusing on the remarkable effects of beige adipocytes to clear liver triglyceride and restore liver insulin sensitivity in obese mice. First, we address in Aim 1 whether the effects of beige adipocytes on systemic metabolism actually require thermogenesis, a burning issue in the field. We will use two methods (CRISPR with DNA template as well as AAV) to selectively enhance expression of UCP1 or creatine kinase CKB (9) or both in the implanted human beige adipose depots. Conversely, we will KO UCP1 or CKB or both to block uncoupling and substrate cycling in human adipocytes prior to implantation. We will determine if systemic effects on metabolic health are dependent on either or both of these thermogenic mechanisms. Second, we aim to test whether reducing free fatty acid entry into liver is a major target(s) of human beige adipocyte signaling, as well as identify the molecular entities that mediate the crosstalk. Thus, Aim 2a takes advantage of new data we obtained from liver mRNA of adipose- selective Nrip1KO mice, showing decreased expression of CD36, which facilitates fatty acid uptake into hepatocytes. Aim 2b takes advantage of our RNAseq data of both Nrip1KO beige adipose tissue and livers from such mice, providing an initial predicted mouse peptide secretome database for functional studies of candidates that signal to liver. We propose a comprehensive “omics” approach to identify secreted peptides, lipids, and metabolites from human beige adipocytes. Combined with state-of-the-art CRISPR and siRNA techniques to determine functionality of candidate signaling factors in vivo, we propose to uncover the factors and their molecular mechanisms that alleviate metabolic disease by human beige adipocytes.


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 = $823,098 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/17/2026	COMPETING CONTINUATION	$823,098
														Subtotal = $823,098

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	9/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $623,634 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/26/2024	NON-COMPETING CONTINUATION	$623,634
														Subtotal = $623,634

Issue Date FY: 2023 ( Subtotal = $645,361 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/30/2023	NON-COMPETING CONTINUATION	$645,361
														Subtotal = $645,361

Issue Date FY: 2022 ( Subtotal = $641,240 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/17/2022	NON-COMPETING CONTINUATION	$641,240
														Subtotal = $641,240

Issue Date FY: 2021 ( Subtotal = $649,900 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/17/2021	NEW	$649,900
														Subtotal = $649,900

Grand Total All Awards = $3,383,233

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CRISPR-enhanced adipocyte browning to improve glucose tolerance in obesity and diabetes

Award Number: R01DK130852

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: 09/17/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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