Hypothalamic gangliosides in the regulation of body weight and adipose tissue homeostasis

• Applicant: Dr. Viola Nordström
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249615253

The prevalence rates of obesity and associated co-morbidities, such as cardiovascular diseases and diabetes type II, are continuously rising worldwide. Thus, major research effort has been put into understanding underlying molecular mechanisms in order to develop prevention or treatment strategies. Energy homeostasis and body weight are regulated by neurons chiefly located in the hypothalamus. The hypothalamic arcuate nucleus (Arc) contains neuronal subpopulations responding to peripheral energy signals, such as leptin or insulin. Neurons sensing these signals adapt firing and neuropeptide expression in order to adjust peripheral energy expenditure to energy intake. Recently, we have unraveled a novel mechanism how hypothalamic neurons regulate body energy homeostasis. Mice with forebrain-specific deletion of glucosylceramide synthase (GCS; gene Ugcg), the key enzyme in ganglioside biosynthesis, develop progressive obesity and hypothermia. Gangliosides are lipid components of cellular membranes. Ganglioside-depleted neurons of these mice are no longer responsive to leptin. We found that gangliosides closely interact with leptin receptors and thereby modulate signal transduction, which is inhibited in ganglioside-deficient hypothalamic neurons. We have confirmed the role of the Arc in these mice by virus-mediated GCS re-expression. However, we could not differ between the neuronal subpopulations located in the Arc. In the present studies, we aim to dissect the role of GCS expression in the regulation of orexigenic NPY/AgRP and anorexigenic POMC neurons. The metabolism and body weight development shall be monitored in mice with specific Cre-mediated Ugcg deletion in either neuronal subpopulation upon either chow or high fat diet feeding. This experimental set-up is intended to unravel a potential role of hypothalamic GCS in adapting the metabolism to a high fat diet challenge. Furthermore, the firing behavior of these neurons shall be analyzed by electrophysiology.Additionally, lipolysis as well as lipogenesis in peripheral adipose tissue shall be investigated in these mice. It has been shown that hypothalamic insulin signaling promotes the downregulation of lipolysis in peripheral adipose tissue. In order to elucidate potential mechanisms underlying decreased fat burning which we have observed earlier, insulin signaling in ganglioside-deficient NPY/AgRP and POMC neurons and subsequent effects on adipose tissue homeostasis shall be analyzed. The aim of the current studies is to understand in more detail how GCS regulates the function of NPY/AgRP and POMC neurons and their subsequent control of body weight. Elucidating novel mechanisms underlying CNS-mediated obesity may contribute to the establishment of novel potential strategies for prevention and treatment of obesity.

• DFG Programme: Research Grants