Abstract
Hypothalamic glucosensing, which involves the detection of glucose concentration changes by brain cells and subsequent release of orexigenic or anorexigenic neuropeptides, is a crucial process that regulates feeding behavior. Arcuate nucleus (AN) neurons are classically thought to be responsible for hypothalamic glucosensing through a direct sensing mechanism; however, recent data has shown a metabolic interaction between tanycytes and AN neurons through lactate that may also be contributing to this process. Monocarboxylate transporter 1 (MCT1) is the main isoform expressed by tanycytes, which could facilitate lactate release to hypothalamic AN neurons. We hypothesize that MCT1 inhibition could alter the metabolic coupling between tanycytes and AN neurons, altering feeding behavior. To test this, we inhibited MCT1 expression using adenovirus-mediated transfection of a shRNA into the third ventricle, transducing ependymal wall cells and tanycytes. Neuropeptide expression and feeding behavior were measured in MCT1-inhibited animals after intracerebroventricular glucose administration following a fasting period. Results showed a loss in glucose regulation of orexigenic neuropeptides and an abnormal expression of anorexigenic neuropeptides in response to fasting. This was accompanied by an increase in food intake and in body weight gain. Taken together, these results indicate that MCT1 expression in tanycytes plays a role in feeding behavior regulation.
Highlights
The hypothalamus controls feeding behavior and glucose homeostasis through the integration of diverse peripheral signals, such as leptin, insulin, ghrelin and glucose
MCT4 is located in the long cellular processes of dorsal β1-tanycytes, which are in close contact with neurons that release mainly the anorexigenic neuropeptides, pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)[8]
In order to assess the ability of the adenovirus to inhibit Monocarboxylate transporter 1 (MCT1), different viral titers were tested on the HEK 293T cell line, which showed that 5 × 107 infectious units per mL (IFU/mL) was the most effective and non-toxic titer
Summary
The hypothalamus controls feeding behavior and glucose homeostasis through the integration of diverse peripheral signals, such as leptin, insulin, ghrelin and glucose. Current evidence shows that neuroendocrine neurons can detect changes in glucose concentrations through direct or indirect mechanisms[11,12,13,14,15,16,17] We propose that these neurons sense glucose changes, at least in part, by an indirect process mediated by MCTs, tanycytes and lactate. In response to an increase in glucose concentration, tanycytes would release lactate, which would act as an intercellular messenger of the metabolic state of the organism, informing and regulating the activity of AN neurons. To test this hypothesis, we generated an adenoviral vector that inhibits the expression of MCT1 (AdshMCT1), which principally transduces tanycytes when is injected in the basal 3V. We evaluated changes in the expression of orexigenic and anorexigenic neuropeptides in response to intracerebroventricular (icv) glucose injection, and determined feeding behavior changes during the fasting-feeding transition
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