# Adipocyte to neuron signaling in thermogenic programming of white adipose tissue

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $582,900

## Abstract

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 re...

## Key facts

- **NIH application ID:** 10341100
- **Project number:** 5R01DK116056-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** MICHAEL P CZECH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $582,900
- **Award type:** 5
- **Project period:** 2019-03-07 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341100

## Citation

> US National Institutes of Health, RePORTER application 10341100, Adipocyte to neuron signaling in thermogenic programming of white adipose tissue (5R01DK116056-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10341100. Licensed CC0.

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