Sphingolipids in the Pathophysiology of Obesity and Diabetes

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 mediates the response to dexamethasone. Aim 3 will examine the in vivo effects of modulating sphingolipid metabolism on overall metabolic function. Accomplishing these aims will break new ground in sphingolipid and metabolic disease research but will also extend our knowledge of how manipulating brown or beige adipose tissue can impact human health.