Inhibition of hypothalamic MCT1 expression increases food intake and alters orexigenic and anorexigenic neuropeptide expression

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.

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

“…Unfortunately, we were not able to evaluate intracellular GLUT2 expression by immunohistochemistry; therefore, it is not known whether possible changes in GLUT2 localization mediated by the transduction contributed to the loss of function. Our present results and previous findings (Elizondo‐Vega et al, 2016) indicate that injection of the adenovirus in the basal 3V results in preferential transduction in ependymal cells and tanycytes but not in neurons or astrocytes. Nevertheless, other authors have reported that serotype 5 adenoviruses exhibit a glial tropism (Cazzin et al, 2010; Chen et al, 2009).…”

“…We have previously shown that 3V injection of an adenovirus with the same capsid transduces mainly tanycytes (Elizondo‐Vega et al, 2016). To corroborate that this also occurs with Ad‐shGLUT2, we used spectral confocal microscopy to evaluate EGFP expression (green), the tanycyte marker, anti‐vimentin (red), and the adult neuronal marker, NeuN (magenta) (Figure 2a–l).…”

“…A Meal Event (ME) was defined as one or more episodes longer than 5 sec and no longer than 15 min, followed by a meal interval (MI). The minimum MI was defined as 10 min, as previously described (Elizondo‐Vega et al, 2016). When feeding episodes were longer than 30 min, they were considered a new meal.…”

Hypothalamic Neurogenesis as an Adaptive Metabolic Mechanism

“…In the hypothalamus, the arcuate nucleus (AN) is composed of clustered neuronal populations that inhibit or initiate food intake through the release of anorexigenic or orexigenic peptides, respectively (Schwartz et al, 2000). There is great interest in understanding the precise molecular and cellular mechanisms that control glucosensing, especially given that diabetes and obesity may be induced by a dysregulation in this process (Elizondo-Vega et al, 2016). …”

“…They also express the molecular machinery that permits glucose sensing (García et al, 2003; Cortés-Campos et al, 2011; Orellana et al, 2012) and transmit signals to AN neurons (Elizondo-Vega et al, 2016). Due to their privileged position in the hypothalamus, tanycytes can also detect mitogenic and neurodifferentiating signals present in the peripheral blood or in the CSF (Robins et al, 2013; Chaker et al, 2016).…”