Body weight and energy homeostasis are regulated by leptin receptor interactions with gangliosides, a class of plasma membrane lipids, in forebrain neurons of mice.
Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene ( Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.
Obesity is a growing health threat that affects nearly half a billion people worldwide, and its incidence rates in lower income countries are rising dramatically. As obesity is a major risk factor for type II diabetes and cardiovascular disease, significant effort has been put into the exploration of causes, prevention, and potential treatment. Recent research has demonstrated that a region of the brain called the hypothalamus is a major integrator of metabolic and nutrient signals, adapting food intake and energy expenditure to current metabolic needs. Leptin or insulin receptors located in the plasma cell membrane of neurons sense energy signals from the body. They transmit this information inside the cell, which then regulates neuronal function. In this study, we show that leptin receptors interact with gangliosides, a class of plasma membrane lipids. This interaction is a prerequisite for proper receptor activation. Consequently, ganglioside loss in hypothalamic neurons inhibits leptin receptor signal transduction in response to energy metabolites. Furthermore, mice lacking gangliosides in distinct forebrain areas, amongst them the hypothalamus, develop progressive obesity and hypothermia. Our results suggest a previously unknown regulatory mechanism of plasma membrane lipids for hypothalamic control of body weight.