# Roles of Sphingolipids in the Pathophysiology of Obesity and Diabetes

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2020 · —

## Abstract

The rise in obesity has led to increased prevalence of metabolic disease including diabetes, fatty liver disease,
cardiovascular disease, and others. Veterans suffer from these diseases at a disproportional rate relative to
the general population. Additionally, obesity and diabetes are strongly linked with post-traumatic stress
disorder, which, based on recent research is now actually considered predictive of diabetes. Scientists now
posture that obesity per se is not deleterious to health, but it is the dysfunction of adipose tissue that leads to
disease. Healthy adipose tissue stores and releases energy appropriately, and secretes endocrine factors that
communicate with peripheral organs and tissues to regulate metabolism. However, unhealthy adipose tissue
has limited capacity for lipid storage, and is often stretched to that limit, when it becomes inflamed, leading to
disruption of many important processes. What determines whether adipose tissue is ‘healthy’ or ‘unhealthy’?
It has become increasingly evident that increased adipocyte size is linked with diabetes. Adipocyte size is also
inversely proportional to the hyperplastic potential of adipose tissue. That is, when new adipocytes can be
made via cell hyperplasia, adipocyte size stays normal; when a limit to hyperplasia occurs, adipocyte size
swells to handle the lipid load. Therefore, we might conclude that ability to proliferate adipocytes is key to
metabolic health.
 Adipocytes arise from mesenchymal stem cells (MSCs), pluripotent cells that can also become muscle,
bone cartilage, and other tissue types. How do these cells ‘decide’ which differentiation pathway to follow?
While some pathways that regulate adipocyte differentiation (or adipogenesis) are known, the factors that
regulate these pathways and thus determine cell fate are poorly understood. We have identified a potentially
novel adipogenic signal, namely, sphingosine-1-phosphate (S1P). This molecule signals through g protein-
coupled receptors to elicit a variety of cell outcomes. There are also receptor-independent functions for
sphingosine-1-phosphate. Because our previous work led us to hypothesize that this molecule and therefore
the enzyme that synthesizes it, Sphingosine Kinase 1 (SK1), may have a role in adipocytes, we made a mature
adipocyte-specific SK1-deletion mouse. We found that these animals have a basal phenotype much like
metabolic syndrome, but they are not obese. Specifically, they are insulin resistant, have high circulating levels
of leptin and insulin, and show signs of non-alcoholic fatty liver disease. Further investigation revealed
upregulation of osteo- and chondrogenic pathways and signaling in adipose tissue of these animals, which
supports that they exhibit a defect in adipogenesis. We hypothesize that sphingosine-1-phosphate,
intracellularly or in the extracellular milieu, participates in creating the adipose tissue microenvironment to
promote adipogenesis in adipogenic precursors deriving from MSCs...

## Key facts

- **NIH application ID:** 9898216
- **Project number:** 5I01BX000200-11
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Lauren Ashley Cowart
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898216

## Citation

> US National Institutes of Health, RePORTER application 9898216, Roles of Sphingolipids in the Pathophysiology of Obesity and Diabetes (5I01BX000200-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898216. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*