# Mechanisms of fat regulation by conserved anti-obesity genes

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $387,614

## Abstract

Obesity affects a majority of American adults, with diverse and significant detrimental effects on human health.
Despite a major role for genetic background in obesity, only a small number of the human genes that
predispose individuals to obesity have been identified. Understanding the pathways that control storage of
body fat will be crucial for pinpointing genes likely to cause susceptibility to this disease. The long-term goal is
to identify genes whose activities can be modified to prevent or treat human obesity. The goals of this
application are to elucidate the mechanism by which the related RNA-binding proteins Spen and Nito regulate
adiposity, and to identify other candidates for cell-autonomous regulation of adiposity. A fruit fly model has
been developed to dissect the tissue specificity of gene function in the regulation of body fat levels, as well as
new tools to parse out the contributions of behavioral alterations and to directly measure rates of fat
incorporation into stores. A complementary approach using cultured cells will directly translate findings in the
fly model to functions in mammalian fat storage. The central hypothesis is that genes acting autonomously in
the fruit fly fat-storage tissue (the fat body, FB) to control levels of body fat will play conserved roles in
mammalian fat storage. This idea is supported by the applicant's previous success in identifying such genes,
and by preliminary data analyzing specific candidate genes, like Spen. The rationale for this project is that
regulatory pathways in fat storage tissues must respond to organismal cues to control levels of stored fat, and
that identifying key genes acting in these pathways may translate directly to insights into genetic
predispositions to human obesity. This model will be tested by pursuing three specific aims: (1) Test the
hypothesis that Spen and Nito function in an opposing manner to regulate body fat. (2) Test the hypothesis that
Spen/Nito regulate energy balance by binding specific RNAs to alter gene expression; and (3) Identify
candidate genes for novel, conserved autonomous regulators of fat storage. In Aim 1, we will determine the
mechanistic basis of defects leading to altered fat in fly larvae lacking Spen and/or Nito, two RNA-binding
proteins in the same family known to modulate transcriptional output of other pathways but never before
implicated in the control of adiposity. In Aim 2, we test a model that Spen and Nito bind specific RNAs to target
specific metabolic target genes for transcriptional control. In the Aim 3, the mouse orthologs of fly genes that
directly regulate fat storage in the FB (including Shep, Rala and NFAT) will be analyzed functionally in cultured
mouse adipocytes to identify those that also control mammalian fat storage in an autonomous manner. This
innovative combination of approaches will uncover new roles for genes whose functions in fat regulation are
currently unknown. The significance of this proposal lies in its...

## Key facts

- **NIH application ID:** 9853011
- **Project number:** 5R01DK106177-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Tania Reis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,614
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853011

## Citation

> US National Institutes of Health, RePORTER application 9853011, Mechanisms of fat regulation by conserved anti-obesity genes (5R01DK106177-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9853011. Licensed CC0.

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