Abstract: In this thesis the questions “do enteric neurons adapt to survive in conditions of obesity/type 2-diabetes (T2D) related metabolic imbalances? Or do they die?” are asked. Obese and T2D patients have high rates of gastrointestinal (GI) symptoms. The GI tract comprises the body’s largest surface to the outside environment; it performs diverse and complex roles in an ever changing external environment. It has evolved into a fine tuned sensory organ, with a complex network of sensory-, taste-, baro-, mehcano- and pathogen recognizing receptors (PRR). The presence of PRRs allows the GI tract to mediate and modulate immune responses, in response to both pathogens and toxins present in our microbiota. The microbiota is shaped by our diet, as well as our genetics. The fluid adaptation and control of the GI tract is mediated by the enteric nervous system (ENS). ENS is an extensive interconnected network of neurons and glia cells, controlling intestinal motility, secretion and blood flow. It harbors a neurotransmitter variety and receptor diversity enabling interactions with neurons, immune, endocrine and intestinal cells as well as with luminal factors. Results show that mice fed a high fat diet (HFD) for 6 months have a significant loss of enteric neurons. To evaluate metabolic factors known to be altered in the obese/T2D-condition (ODC), we used isolated enteric neurons. We noted that palmitic acid (PA), a lipid known to be increased in ODC caused a significant loss of enteric neurons, through mechanisms involving deranged energy metabolism and the purinergic P2Y13 receptor. In ODC an increased permeability of the intestinal barrier causes increased translocation of lipopolysaccharide (LPS) to the circulation and initiation of immune responses. We found that exposing cultured enteric neurons to LPS caused neuronal loss through activation of AMP activated protein kinase. Glucagon-like peptide (GLP) 1 and 2 are involved in satiety, insulin release and intestinal barrier function. Both GLPs are reduced in ODC. We showed a great neuroprotective potential of the hormones. Based on these findings, HFD-induced enteric neuronal loss is suggested to be a culmination of several factors, including increased PA- and LPS-exposures and a decreased GLP level, leading to dysregulation and altered function of enteric neurons.