Inhibition of Hypothalamic MCT4 and MCT1–MCT4 Expressions Affects Food Intake and Alters Orexigenic and Anorexigenic Neuropeptide Expressions

Abstract

Feeding behavior regulation is a complex process, which depends on the central integration of different signals, such as glucose, leptin, and ghrelin. Recent studies have shown that glial cells known as tanycytes that border the basal third ventricle (3V) detect glucose and then use glucose-derived signaling to inform energy status to arcuate nucleus (ARC) neurons to regulate feeding behavior. Monocarboxylate transporters (MCT) 1 and MCT4 are localized in the cellular processes of tanycytes, which could facilitate monocarboxylate release to orexigenic and anorexigenic neurons. We hypothesize that MCT1 and MCT4 inhibitions could alter the metabolic communication between tanycytes and ARC neurons, affecting feeding behavior. We have previously shown that MCT1 knockdown rats eat more and exhibit altered satiety parameters. Here, we generate MCT4 knockdown rats and MCT1-MCT4 double knockdown rats using adenovirus-mediated transduction of a shRNA into the 3V. Feeding behavior was evaluated in MCT4 and double knockdown animals, and neuropeptide expression in response to intracerebroventricular glucose administration was measured. MCT4 inhibition produced a decrease in food intake, contrary to double knockdown. MCT4 inhibition was accompanied by a decrease in eating rate and mean meal size and an increase in mean meal duration, parameters that are not changed in the double knockdown animals with exception of eating rate. Finally, we observed a loss in glucose regulation of orexigenic neuropeptides and abnormal expression of anorexigenic neuropeptides in response to fasting when these transporters are inhibited. Taken together, these results indicate that MCT1 and MCT4 expressions in tanycytes play a role in feeding behavior regulation.

GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates

“…In turn, their elongated processes project toward the arcuate nucleus (ARC), where feeding-regulating neurons reside 10 , suggesting that tanycytes could convey metabolic signalling to ARC neurons. Supporting this intercellular communication, we have shown that disruption of several tanycyte proteins involved in glucose metabolism, including GLUT2 11 , GK 12 , and MCT1-4 13 , 14 , increase food intake in rats. This led us to propose that glucose from the CSF is taken by tanycytes using GLUT2, which is then metabolized to lactate with the participation of GK.…”

“…To evaluate the role of lactate and βHB over hypothalamic neuronal activity, we measured the expression of feeding-controlling neuropeptides in hypothalamic cultures containing mainly neurons by RT-qPCR (Figure 2 A), as prevoulsy done 11 , 14 , 18 . These cultures were maintained in 1 mM glucose and then we measured changes in neuropeptide mRNA levels 2 h post-stimulation as a consequence of neuropeptides released in response to different concentrations of glucose, lactate, and βHB.…”

“…Using different approaches, we and others have proposed that the lactate released by tanycytes in response to glucose can mediate an anorexigenic response in the ARC 14 , 16 , 19 . However, the role of tanycyte-released βHB at the hypothalamic level is unknown.…”

The Role of Tanycytes in the Hypothalamus-Pituitary-Thyroid Axis and the Possibilities for Their Genetic Manipulation

“…Adenoviral vectors were employed to express shRNAs against Mct1 [66,67], Mct4 [67], Gk [68], Glut2 [69], and Glut6 [70], driven by a human H1 promoter. These studies provided evidence that tanycytes are involved in the transport and metabolism of glucose as well as in metabolic sensing in the MBH.…”

“…These studies provided evidence that tanycytes are involved in the transport and metabolism of glucose as well as in metabolic sensing in the MBH. A knockdown of the glu- [66,67]. It has been suggested that neurons of the MBH can sense the energy status of tanycytes as reflected by extracellular lactate concentrations [71].…”