# Adipose FHL1 in energy homeostasis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $406,396

## Abstract

SUMMARY
Tremendous advances have been made in the study of adipose biology but there are gaps in our understanding
of adipose development and functions. The long-term goal of our research is to understand how adipose tissues
regulate whole-body energy metabolism, insulin sensitivity and glucose homeostasis. To achieve these goals,
we have developed cellular and animal models to study the effects of gene perturbations in relation to adipose
tissues development. One such gene is Four-and-half-LIM domain 1 (FHL1), a protein highly expressed in
skeletal and cardiac muscles, and has recently been implicated in human adipose tissue development. A case
report on a 15-year old patient with a complete deletion of FHL1 with adjacent MAP7D3 gene exhibited a near
total loss of adipose tissues accompanied by muscular hypertrophy, rigid spine and short stature. The specific
role of FHL1 in adipose development and function is unknown. In preliminary experiments, we identified FHL1
as a major co-transcription factor of PPARg, suggesting a role in transcriptional regulation of adipose tissues. To
mimic the loss of adipose tissues in the human patient, we created a mouse model where FHL1 is globally
deficient. Whole body Fhl1 knockout mice were resistant to diet-induced obesity (DIO). Interestingly, a previous
study has shown that mice lacking a related paralog, FHL2, are also resistant to DIO. We found that FHL1
deficiency in murine preadipocytes partially attenuated differentiation into adipocytes, and a single amino acid
substitution from tryptophan to serine at position 122 within FHL1 specifically abrogated PPARg isoform 2
(PPARg2) expression, but not isoform 1 (PPARg1). In agreement, knockdown of FHL1 in human adipocytes
preferentially reduced PPARg2 expression, but not PPARg1. It has been reported that PPARg2 is adipose-
specific, necessary and sufficient in activation of adipogenesis in fibroblast. In addition to activation of PPARg,
FHL1 cooperates with PPARg in activation of PPARg-dependent gene expression. Based on our preliminary data,
we hypothesized that FHL1 regulates adipocyte differentiation, at least in part, through transcriptional regulation
of PPARg. This proposal seeks to investigate the cellular, molecular and physiological mechanisms by which
FHL1 regulates adipose tissue development and energy homeostasis. Specific Aim 1 will examine the roles of
FHL1 and FHL2 in murine adipocyte differentiation. Specific Aim 2 will address the underlying molecular
mechanisms linking FHL1 and transcriptional regulation of adipocyte differentiation. Specific Aim 3 will
investigate the in vivo functions of FHL1 in adipose-specific knockout mice and in human transplant models.
Together, the proposed experiments will provide mechanistic insights into adipose biology, pathophysiology of
obesity, potentially lead to novel therapeutic strategies for obesity and related metabolic diseases.

## Key facts

- **NIH application ID:** 10922811
- **Project number:** 5R01DK136755-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Frederick Anokye-Danso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,396
- **Award type:** 5
- **Project period:** 2023-09-06 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922811

## Citation

> US National Institutes of Health, RePORTER application 10922811, Adipose FHL1 in energy homeostasis (5R01DK136755-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10922811. Licensed CC0.

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