Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

The hypophagic response to heat stress is not mediated by GPR109A or peripheral ß-OH butyrate.

Rising temperatures resulting from climate change will increase the incidence of heat stress, negatively impacting the labor force and food animal production. Heat stress elevates circulating ß-OH butyrate, which induces vasodilation through GPR109a. Interestingly, both heat stress and intraperitoneal ß-OH butyrate administration induce hypophagia. Thus, we aimed to investigate the role of ß-OH butyrate in heat stress hypophagia in mice. We found that niacin, a ß-OH butyrate mimetic that cannot be oxidized to generate ATP, also reduces food intake. Interestingly, the depression in food intake as a result of 8-h intraperitoneal niacin or 48-h heat exposure did not result from changes in hypothalamic expression of orexigenic or anorexigenic signals (AgRP, NPY, or POMC). Genetically eliminating GPR109a expression did not prevent the hypophagic response to heat exposure, intraperitoneal ß-OH butyrate (5.7 mmol/kg), or niacin (0.8 mmol/kg). Hepatic vagotomy eliminated the hypophagic response to ß-OH butyrate and niacin but did not affect the hypophagic response to heat exposure. We subsequently hypothesized that the hypophagic response to heat stress may depend on direct effects of ß-OH butyrate at the central nervous system: ß-OH butyrate induced hormonal changes (hyperinsulinemia, hypercorticosteronemia, and hyperleptinemia), or gene expression changes. To test these possibilities, we blocked expression of hepatic hydroxyl methyl glutaryl CoA synthase II (HMGCS2) to prevent hepatic ß-OH butyrate synthesis. Mice that lack HMGCS2 maintain a hypophagic response to heat stress. Herein, we establish that the hypophagia of heat stress is independent of GPR109a, the hepatic vagus afferent nerve, and hepatic ketone body synthesis.

Bidirectional influences between neurons and glial cells in the developing olfactory system.

Olfactory systems serve as excellent model systems for the study of numerous widespread aspects of neural development and also for the elucidation of features peculiar to the formation of neural circuits specialized to process odor inputs. Accumulated research reveals a fine balance between developmental autonomy of olfactory structures and intercellular interactions essential for their normal development. Recent findings have uncovered evidence for more autonomy than previously realized, but simultaneously have begun to reveal the complex cellular and molecular underpinnings of key interactions among neurons and glial cells at several important steps in olfactory development. Striking similarities in the functional organization of olfactory systems across vertebrate and invertebrate species allow the advantages of different species to be used to address common issues. Our own work in the moth Manduca sexta has demonstrated reciprocal neuron-glia interactions that have key importance in two aspects of development, the sorting of olfactory receptor axons into fascicles targeted for specific glomeruli and the creation of glomeruli. Studies in vertebrate species suggest that similar neuron-glia interactions may underlie olfactory development, although here the roles have not been tested so directly. Similar cellular interactions also are likely to play roles in development of some other systems in which axons of intermixed neurons must sort according to target specificity and systems in which reiterated modules of synaptic neuropil develop.