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Adipocyte to neuron signaling in thermogenic programming of white adipose tissue

Award Number: R01DK116056
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: 03/07/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Adipocyte to neuron signaling in thermogenic programming of white adipose tissue - Abstract The overarching long term goal of our laboratory is to understand and exploit how adipose tissues exert powerful control over whole body glucose tolerance and insulin sensitivity. Small amounts of mouse brown (BAT) or human “Beige” adipocytes transplanted into recipient mice can improve glucose homeostasis, highlighting the importance of understanding mechanisms of adipose browning. Based on the knowledge that intermediates of the de novo lipogenesis (DNL) pathway display potent signaling functions (e.g., Acetyl CoA as substrate for histone acetylation, transcriptional regulation) and that adipocyte DNL is highly regulated by obesity, fasting, cold exposure, and exercise, we hypothesize that adipocyte DNL is a major regulatory node in metabolism. We aim to interrogate this concept by perturbing this DNL pathway through selective KO of DNL enzymes ATP citrate lyase (ACLY) and fatty acid synthase (FASN). Our preliminary data encourage this approach by revealing that FASN KO upregulates adipocyte neurotrophic factor Neuregulin 4 (Nrg4) and enhances expansion of sWAT sympathetic neurons (SNS), even at thermo-neutrality (30C). Thus, DNL metabolites (Acetyl CoA, Malonyl CoA) or DNL product (Palmitoyl CoA) appear to be intimately linked to controlling adipose SNS activity, adipose energy expenditure and whole body glucose homeostasis. Based on these data, this project seeks to determine the cellular and molecular mechanisms whereby adipocytes can signal to localized SNS neurons and promote the development of Beige adipocytes in sWAT. Aim 1 will determine whether Beige adipocytes in iAdFASNKO mice are derived by direct “conversion” of mature white to beige adipocytes OR by paracrine signaling to induce differentiation of progenitor cells to Beige adipocytes. To address underlying mechanisms, Aim 2 will determine whether Nrg4 (and Negr1, which may also be upregulated) mediates the effect of FASN-depleted adipocytes to cause expansion of the SNS in vivo. This Aim is based on exciting preliminary data showing that conditioned media from such adipocytes cause marked neurite outgrowth in PC-12 neurons in vitro, which is inhibited by Nrg4 silencing. New technology we developed will be used to delete adipocyte Nrg4 and Negr1 using CRISPR-based nanoparticles prior to implantation into recipient mice and analysis of their effects on SNS innervation. Finally, Aim 3 tests whether adipocyte DNL intermediate metabolites Acetyl CoA/Malonyl CoA in iAdFASNKO mice initiate signaling to cause Nrg4 expression and SNS expansion. These adipocyte metabolites in iAdFASNKO mice, and their acetylation and malonylation of cellular proteins, will be reversed by KO of ATP citrate Lyase (ACLY), which generates the Acetyl CoA, in double KO mice. Identifying the DNL intermediates that modulate adipocyte function will enable defining their underlying mechanisms. Together, these experiments have high potential to define novel signaling pathways driven by DNL metabolites that regulate adipose browning and new therapeutic strategies for type 2 diabetes.


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 = $0 )
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $582,900 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/30/2023	NON-COMPETING CONTINUATION	$582,900
														Subtotal = $582,900

Issue Date FY: 2022 ( Subtotal = $582,900 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/29/2022	NON-COMPETING CONTINUATION	$58,290
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/6/2022	NON-COMPETING CONTINUATION	$524,610
														Subtotal = $582,900

Issue Date FY: 2021 ( Subtotal = $582,900 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/4/2021	NON-COMPETING CONTINUATION	$582,900
														Subtotal = $582,900

Issue Date FY: 2020 ( Subtotal = $582,900 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/26/2020	NON-COMPETING CONTINUATION	$58,290
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/23/2020	NON-COMPETING CONTINUATION	$524,610
														Subtotal = $582,900

Issue Date FY: 2019 ( Subtotal = $582,900 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/8/2019	NEW	$582,900
														Subtotal = $582,900

Grand Total All Awards = $2,914,500

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Adipocyte to neuron signaling in thermogenic programming of white adipose tissue

Award Number: R01DK116056

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: 03/07/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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