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

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.

Adenovirus-mediated suppression of hypothalamic glucokinase affects feeding behavior.

Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic ß-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART and orexigenic AgRP and NPY neuropeptides were altered in GK knockdown animals. Similarly, food intake, meal duration, frequency of eating events and the cumulative eating time were increased, whereas the intervals between meals were decreased in GK knockdown rats, suggesting a decrease in satiety. Thus, GK expression in the ventricular cells appears to play an important role in feeding behavior.

Serum 1,25-Dihydroxyvitamin D as a Biomarker of the Absence of Hypercalciuria in Postsurgical Hypoparathyroidism.

Context: Hypercalciuria is an adverse event of postsurgical hypoparathyroidism treatment that can lead to renal complications. The collection of 24-hour urine to detect hypercalciuria is often considered unreliable. Objective: The purpose of this study was to find useful predictive biomarkers of hypercalciuria in patients with permanent postsurgical hypoparathyroidism receiving treatment with oral calcium and calcitriol supplements. Design and Setting: The investigation was designed as a prospective cross-sectional study. An outpatient hospital clinic served as the study setting. Patients: Fifty-four consecutive observations were made of 34 stable outpatients with postsurgical hypoparathyroidism taking oral calcium and calcitriol supplements, and 17 adult controls without hypoparathyroidism. Intervention: There were no interventions. Main Outcome Measure: Hypercalciuria was defined as 24-hour urine calcium >300 mg. Results: Patients without hypercalciuria (n = 21) vs those with hypercalciuria (n = 33) had lower levels of serum 1,25-dihydroxyvitamin D (33.5 ± 11.9 pg/mL vs 45.8 ± 9.5 pg/mL; P < 0.001), similar albumin-corrected serum calcium (8.3 ± 0.5 vs 8.6 ± 0.5 mg/dL; P = nonsignificant), and serum parathyroid hormone (12.5 ± 5.7 vs 10.7 ± 6.8 pg/mL; P = nonsignificant). Multiple linear regression analysis showed an independent relationship between 1,25-dihydroxyvitamin D and urinary calcium excretion (B = 6.2 ± 1.423; P < 0.001). A cutoff value of 33.5 pg/mL for serum 1,25-dihydroxyvitamin D to predict the absence of hypercalciuria had 100% sensitivity and 63.6% specificity, and the area under the receiver operating characteristic curve was 0.797. No patients with serum 1,25-dihydroxyvitamin D levels of <33.5 pg/mL presented with hypercalciuria, regardless of the level of albumin-corrected serum calcium. Conclusions: Routine measurement of serum 1,25-dihydroxyvitamin D may be useful as a biomarker to predict the absence of hypercalciuria in patients with permanent postsurgical hypoparathyroidism who are receiving treatment with oral calcium and calcitriol supplements.