# Sphingolipids in the Pathophysiology of Obesity and Diabetes

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2022 · —

## Abstract

Obesity, diabetes, and their pathological outcomes including cardiovascular disease, liver disease, and
others, are a major burden on the Veteran population and the VA health system. The overarching goal of our
research is to identify deleterious metabolic pathways linking obesity to downstream pathophysiology. Over
the duration of this project (started with the first Merit award in 2009) we have determined that obesity and
diabetes change sphingolipid metabolism linking obesity to deleterious outcomes in heart and liver. At the crux
of lipid metabolism and metabolic disease lies adipose tissue. Adipose tissue, while once thought to be an
inert energy storage depot, is now recognized to have endocrine properties that are blunted in obesity leading
to negative health outcomes, and it is also recognized that inflammation and over-expansion of adipose tissue
through adipocyte hypertrophy underlies much obesity-related pathophysiology.
 The complexity of adipose biology is continuing to emerge. In addition to the ‘white’ adipose tissue
depots that do in fact serve to store and release energy, adipose tissue can also be ‘brown’—these ‘brown’
depots are critical for thermoregulation in infants and rodents, and, until recently, were not thought to exist in
adult humans. Brown adipose tissue is beneficial for the organism as it uses fatty acids to generate heat, and it
is so metabolically active that its energy consumption can lower circulating glucose and triacylglycerols,
thereby improving metabolic health. Moreover, brown adipose also secretes beneficial hormones that
contribute to its positive effects. While brown adipose tissue depots in adult humans are small, it has recently
become apparent that white adipose tissue, i.e. abdominal and subcutaneous adipose, can be induced to a
brown-like state. Stimuli such as cold exposure, exercise, and adrenergic receptor stimulation can cause white
adipocytes to accrue brown-like properties. The plasticity of this so-called ‘beige’ adipose tissue is attractive
as a potential method by which to improve metabolic health. Glucocorticoids, widely used for various ailments
in the Veteran population, suppress thermogenic adipose, which may underlie the well known obesogenic
properties of glucocorticoid treatment.
 Molecular mechanisms by which white adipocytes convert to brown-like or ‘beige’ adipocytes remain
incompletely understood; however, we recently found that Sphingosine Kinase 1, a lipid kinase that generates
a class of lysophospholipids, is important for cold-induced browning. This proposal seeks to understand this
process and determine whether this pathway can be targeted to improve metabolic homeostasis by a series of
studies organized into 3 aims. Aim 1 will determine the molecular interactions that link Sphingosine Kinase 1
with browning of white adipose tissue. Aim 2 will test whether modulation of Sphingosine Kinase 1 can
suppress thermogenic function of bona-fide brown adipose tissue and whether this...

## Key facts

- **NIH application ID:** 10369950
- **Project number:** 2I01BX000200-12A1
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Lauren Ashley Cowart
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2009-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369950

## Citation

> US National Institutes of Health, RePORTER application 10369950, Sphingolipids in the Pathophysiology of Obesity and Diabetes (2I01BX000200-12A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10369950. Licensed CC0.

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