Neuronal Control of Metabolism
The overall aim of our research group is to unravel the fundamental regulatory principles of how neurons sense nutritional cues and then to determine the neurocircuitry responsible for the coordinated adaptation of behavioral and autonomic outputs. Moreover, we aim to identify molecular and physiological mechanisms for alterations in these pathways during the development of obesity and type-2 diabetes mellitus. Finally, we are also investigating the molecular basis of how genetic variants link with obesity as well as how metabolic disorders affect these fundamental regulatory principles. The ultimate aim of our research is to discover novel therapeutic targets for the development of treatment of metabolic disorders.
(1) Regulatory principles of the neurocircuitry in control of energy and glucose homeostasis
During the last decade, our group has revealed the fundamental importance of the core melanocortin circuitry comprising agouti-related peptide- (AgRP) and proopiomelanocortin- (POMC) expressing neurons in the arcuate nucleus of the hypothalamus in the control of feeding and glucose homeostasis. Specifically, we have investigated how insulin regulates neuropeptide expression and neuronal excitability in these cells to adapt energy intake, expenditure, as well as nutrient partitioning across different organs to circulating glucose concentrations and systemic fat storage. Through the use of pharmacogenetic and optogenetic approaches as well as transcriptional profiling of activated neurons, we aim to extend our current understanding about the fundamental functional architecture of these neurocircuits in the control of energy and glucose homeostasis.
(2) Inflammatory and lipotoxic signaling pathways in obesity and type-2 diabetes mellitus
Over the last years, it has become evident that obesity represents a state of chronic low-grade inflammation. This inflammation is triggered either through the release of cytokines from innate immune cells that are activated in obesity, or by the ectopic accumulation of lipid species that can trigger activation of inflammatory signaling cascades, such as c-Jun N-terminal kinase (JNK) and the inhibitor of NFκB kinase (IKK), to impair insulin and leptin action. To date, our group has unraveled the fundamental mechanisms on how obesity-associated increases in interleukin 6-signaling control metabolism through its action in peripheral tissues, such as liver, skeletal muscle, macrophages, as well as in the CNS. Moreover, we have determined the specific role for fatty acid-induced TLR-dependent signaling in the CNS in the development of obesity-associated insulin and leptin resistance. More recently, we have defined the specific role of JNK and IKK activation in AgRP neurons in the arcuate nucleus of the hypothalamus towards manifestation of key aspects of the metabolic syndrome. We are also investigating lipotoxicity-induced insulin and leptin resistance. So far, we have deciphered the unique role for C16-containing ceramides during the development of obesity and insulin resistance and we are currently investigating the underlying molecular mechanisms through which C16 ceramide accumulation in obesity contributes to the manifestation of insulin and leptin resistance both in peripheral organs as well as in the CNS.
(3) Role of genetic variants in altered energy homeostasis
During the last decade, genome-wide association studies have revealed novel candidate genes whose variants are associated with obesity and type-2 diabetes mellitus. One of the strongest linked gene variants associated with obesity resides in the fat mass and obesity-associated (FTO) gene. Our group has demonstrated through the generation and characterization of FTO-deficient mice the fundamental role for FTO in the control of energy homeostasis. More recently, we have demonstrated that FTO acts as a methyl-6-adenosine demethylase (m6A) and single-stranded nucleic acids, specifically mRNAs in the CNS in vivo. Ablation of FTO results in increase and m6A modification of specific mRNA molecules, partly affecting their rate of translation. We also found that FTO-dependent m6A modification of mRNAs affects core components of dopaminergic signaling, and therefore, FTO-deficient mice recapitulate key phenotypes associated with altered dopaminergic transmission. Ongoing studies aim to investigate additional mechanisms as a first step to determining how FTO affects other neuronal circuits of critical importance in the control of energy and glucose homeostasis.