# Role of Ceramide Regulated Fgf13 in AdiposeT issue Biology

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $386,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Dyslipidemia and insulin resistance predispose individuals to development of diabetes, cancer, myocardial
infarction, and stroke. A large body of evidence suggests that a class of toxic lipids, termed ceramides,
contribute to these metabolic impairments and the ensuing development of these metabolic disorders.
Understanding the role of these lipids in the events that drive metabolic diseases holds great promise for
developing new therapies to treat these debilitating conditions. We conducted a series of studies ablating the
enzymes required for their production in different body locales to discern which tissues were most sensitive to
ceramides. These studies revealed that the lipid has strong and unanticipated effects in adipose tissue. In
particular, whole-body, adipose and brown adipose tissue-specific inhibition/deletion of serine
palmitoyltransferase (Sptlc), the first enzyme in the enzymatic cascade that drives sphingolipid biosynthesis, in
mice markedly altered adipose morphology and metabolism, particularly in subcutaneous and brown adipose
tissue. We subsequently excised another gene in the pathway (i.d. dihydroceramide desaturase-1 (Degs1)) from
adipose tissue, determining that it elicited a similar spectrum of metabolic improvements. These data indicate
that ceramides serve as signals of nutrient excess that alter the metabolic activity of mature adipocytes and
subsequently the entire organism. Using microarray screens, we sought to identify ceramide-regulated genes in
adipose tissue. The candidate obesity gene Fgf13 was one of the only two transcripts that met the following
criteria: (a) increased in mouse subcutaneous white adipose (sWAT) and epididymal white adipose (eWAT) after
high fat feeding (HFD); (b) decreased in these depots when the mice were treated with the SPT inhibitor myriocin;
(c) decreased in these depots following WAT-specific Sptlc2 depletion; and, (d) decreased in primary adipocytes
following myriocin treatment in vitro. We then investigated the function of this protein in vitro and in vivo.
Preliminary data using knockdown or knockout approaches suggested that Fgf13 had cell-autonomous,
adipocyte-specific, diet-regulated effects on mitochondrial function and thermogenesis. Moreover, mice lacking
Fgf13 in adipocytes were resistant to obesity. These data support our hypothesis that FGF13 is a ceramide
effector that controls the metabolic activity of mature adipocytes. We will test this idea with the following Specific
Aims: 1] to determine the role of FGF13 as a modulator of adipose tissue metabolism and thermogenesis in
vivo; 2] to determine the molecular mechanisms linking FGF13 to adipocyte metabolism; and 3] to determine
the molecular mechanisms by which b-adrenergic agonists regulate ceramide production and FGF13 expression
in primary adipocytes. The findings obtained from these studies could reveal a novel ceramide effector that
influences metabolic rate.

## Key facts

- **NIH application ID:** 10341156
- **Project number:** 5R01DK124326-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Bhagirath Chaurasia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341156

## Citation

> US National Institutes of Health, RePORTER application 10341156, Role of Ceramide Regulated Fgf13 in AdiposeT issue Biology (5R01DK124326-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10341156. Licensed CC0.

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