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Principal Investigator: ROBERT G BENNETT
Organization: OMAHA VA MEDICAL CENTER
Fiscal Year: 2023
Funding agency: Veterans Affairs
Metabolic disorders, such as obesity, are associated with adipose tissue hypoxia, inflammation and fibrosis,
and impaired lipid uptake, causing ectopic lipid uptake other organs, such as the liver. Furthermore, the secreted
adipokine profile changes dramatically, with impaired secretion of antifibrotic factors (e.g. adiponectin), and
elevated release of profibrotic adipokines (e.g. endotrophin, leptin). This alteration in the secretome negatively
affects other organs, elevating the risk of metabolic diseases such as diabetes. Therefore, adipose tissue
dysfunction is a crucial element in the development and progression of metabolic disease.
Our previous work, focused on the antifibrotic role of the hormone relaxin, established that relaxin, through its
receptor RXFP1, reduced established hepatic fibrosis in mice. We discovered that one mechanism for relaxin’s
actions is through selective activation of peroxisome proliferator-activated receptor γ (PPARγ). RXFP1-knockout
mice develop age-related fibrosis in many tissues, but no studies had been conducted in adipose tissue. Our
recent experiments revealed that RXFP1-knockout mice developed age-related fibrosis in the visceral,
subcutaneous and brown adipose tissue, and have increased inflammation and decreased serum adiponectin
levels. Furthermore, we have established for the first time that RXFP1 is expressed by the adipose tissue
macrophages. Nothing is known about the mechanisms by which relaxin protects against adipose tissue fibrosis
or the impairments in function, or in alterations in adipose tissue secretion. Given the importance of adipose
tissue functioning in the maintenance of metabolism, and the importance of its secretome in affecting other
organs, targeting the relaxin pathway represents a novel approach to treating metabolic disease characterized
by adipose tissue dysfunction.
Our long-term goal is to uncover biochemical mechanisms underlying metabolic disease in order to develop
effective treatments. Our central hypothesis for this proposal is that relaxin regulates both adipose tissue and
liver function and thereby promotes normal functioning. This hypothesis is based on the new finding that relaxin
plays a role in adipose fibrosis and function, and our previous findings implicating relaxin in liver fibrosis and
regeneration. The rationale for the proposed studies is that understanding the mechanisms for relaxin’s effects
in these tissues will lead to development of specific targets for treatment. Our experience in endocrinology and
liver disease models, and nanoparticle development, will provide a conducive research environment to
successful completion of the proposed studies. We propose three Specific Aims:
1. Identify the mechanisms for the antifibrotic effects of relaxin in adipose tissue.
2. Determine the effect of the relaxin pathway on the adipose tissue secretome and interorgan signaling to the
liver.
3. Develop relaxin receptor-targeting nanoparticles on adipose tissue fibrosis in vivo.
In Aim 1, we will utilize conditional RXFP1 knockout mice with conjugated linoleic or diet-induced obesity
models to determine the roles of RXFP1 in different adipose tissue cells and their signaling pathways. In Aim 2,
we will conduct proteomics studies to distinguish between secreted factors from conditional RXFP1 knockout
mice. In Aim 3, we will develop adipose tissue-targeting nanoparticles to deliver relaxin and selective PPARγ
agonists for treatment of adipose tissue dysfunction. Successful completion of these Aims will provide critical
insights into the mechanisms regulating adipose tissue fibrosis and function, and will test a new avenue for
treatment. This would provide the potential to combat the current increase in obesity-related diseases and
comorbidities, which is a major issue not only in the population at-large, but particularly in the veteran population.
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