Nutrient Sensing, Gut/Brain Communication in Health and Diseases

Recent data comparing dysregulated pathways in the peripheral nervous system (PNS) of type II diabetic neuropathic individuals have highlighted alterations in lipid nuclear receptors, which may provide insight into the physiological basis of diabetic neuropathy. Liver X Receptors (LXR) α and β are nuclear transcription factors that respond to cholesterol or fatty acid metabolites. LXRs interact with PPAR (peroxisome proliferator activated receptor) or RXR (retinoid X receptor) in liver cells, adipocytes, and macrophages to regulate complex intracellular lipid metabolism, though the physiological and molecular roles of LXRs in nerve system is understudied and obscure. We try to clarify the role of nuclear lipid sensors expressed in the PNS in model of diabetes and in aging model.

Over 70 million Americans are obese, pre-diabetic and 10 -30% of them develop neuropathic pain, a condition that severely impacts quality of life for which there is no disease modifying therapy.

Research using diabetic rodents shows that high circulating glucose and/or dyslipidemia disrupts the peripheral nerve system (PNS) secondary to mitochondrial disruption, impaired calcium homeostasis and neurotransmitter secretion and altered neuroimmune function. Novel mechanism-based treatment is necessary to produce non addictive and individualized therapies for obese and early diabetic patients. Recently, we published that fecal microbiota transplantation (FMT) from lean mice to Western-diet (WD) fed obese mice reduced indices of pain and neuropathy concomitant with an increase in circulating butyrate, PNS immune cell reprogramming and change in calcium homeostasis in PNS neurons. Our data shows that FFAR (Free fatty acid receptor 3), a Gi-coupled receptor that binds butyrate and expressed in sensory neurons and immune cells of WD-fed mice may mediate efficacy, we used novel cell specific tools to test this hypothesis.

The prevalence of obesity and its associated comorbidities such as type 2 diabetes (T2D) continues to rise, and innovative interventions are needed¹. Recent studies have identified the vagus nerve (VN) as a promising target for the treatment of obesity and T2D. The vagus nerve consists primarily of sensory neurons, many of which relay information from the alimentary tract to the brain to regulate behavior, energy balance and glucose homeostasis⁵. More recently, attention has been drawn to the VN because of its role in communicating information from gut microbiome metabolites to the brain. Gut bacteria ferment non-digestible dietary fiber to produce the short-chain fatty acids (SCFA’s) acetate, propionate, butyrate⁶ which can serve as potent signals regulating host physiology⁷. Dietary supplementation of fiber or SCFA’s has been shown to improve glucose tolerance and appetite, and studies suggest that the vagus nerve is required, but the neurobiology underlying this effect is unknown, using vagal genetically modified models we are testing the hypothesis that SCFA are sensed to regulate energy balance and glucose homeostasis.

Previous whole-body knockout studies showed that loss of C2CD5 induced pronounced obesity by modifying food intake behavior or even energy expenditure¹⁴. Our studies demonstrates that C2CD5 is associated with mitochondria and regulates mitochondrial trafficking in neurons and likely other cell types. We are testing the hypothesis that C2CD5 could represent the first protein regulated by metabolic cues and involved in mitochondria trafficking in the brain. C2CD5 may link neuronal dysfunction and metabolic diseases such as obesity and diabetes.