# Illuminating novel roles for the Ldb1 co-regulator in transcriptional regulation of brown adipose function

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $44,100

## Abstract

Project Summary/Abstract
Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. BAT utilizes fatty acids
and glucose for heat production via mitochondrial uncoupling and is thus an attractive therapeutic target for
combatting obesity. Exploiting the unique energy uncoupling capacity of this tissue requires a greater
understanding of underlying BAT transcriptional mechanisms. We recently reported on a transcriptional co-
regulator, LIM domain binding protein 1 (Ldb1), which appears to have novel roles in BAT biology. Ldb1 acts
as a dimerized scaffold allowing for the assembly of transcriptional complexes and is important for the
development and function of many metabolic tissues, including the brain and pancreatic islets. However, direct
roles for BAT-expressed Ldb1 have not been elucidated. I will test the hypothesis that Ldb1 directly impacts
BAT function. Ldb1 deletion in isolated preadipocytes resulted in reduced Ucp1 expression upon induction to
mature adipocytes. Additionally, I developed a mouse model which deleted Ldb1 in thermogenic adipocytes
using a Ucp1-driven Cre recombinase, termed Ldb1ΔBAT. These knockout mice have reductions in BAT-
selective mRNAs including Ucp1 and Elovl3, a result similarly observed in an X9 beige cell line lacking Ldb1.
Ldb1ΔBAT mice were unable to defend body temperature during a cold challenge, suggesting thermogenic
defects. We also observed glucose intolerance in Ldb1ΔBAT mice via intraperitoneal glucose challenge. To
dissect the role of Ldb1 in regulating whole-body physiology, Ldb1ΔBAT will be assessed for changes in energy
expenditure, respiratory quotient, thermogenesis, feeding behavior, locomotor activity, and fuel utilization using
the Comprehensive Lab Animal Monitoring System. Glucose metabolism will be monitored through changes in
fasting blood glucose, intraperitoneal glucose tolerance with BAT-agonist treatment, insulin tolerance test, and
insulin signaling. To determine how the loss of Ldb1 affects brown adipocyte function, lipid content will be
assessed via Oil Red O staining and quantitative real-time PCR for lipogenesis markers. BAT histology will
determine changes to cell size and lipid content. Cellular respiration measurements will determine changes in
mitochondrial function, fatty acid oxidation and glycolytic flux. To elucidate the global transcriptional role of
Ldb1 in BAT gene expression, Ldb1ΔBAT mice will be crossed with a NuTRAP reporter mouse (termed
Ldb1ΔNuBAT) to allow sorting of adipocyte nuclei and mRNA. These sorted fractions will be examined for global
transcriptional changes via RNA-Seq, and bound targets via ChIP-Seq, with the results prioritized based on
genes associated with thermogenesis, glucose and lipid metabolism, and mitochondrial function. Results from
this proposal will inform future studies assessing Ldb1 roles in BAT under metabolic stresses, like high-fat diet
(HFD) as well as elucidating novel Ldb1-interacting transcriptional ...

## Key facts

- **NIH application ID:** 9921202
- **Project number:** 5F31DK121414-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jessica Kepple
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,100
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921202

## Citation

> US National Institutes of Health, RePORTER application 9921202, Illuminating novel roles for the Ldb1 co-regulator in transcriptional regulation of brown adipose function (5F31DK121414-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9921202. Licensed CC0.

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