Abstract
GNPDA2 has been associated with human obesity and type-2 diabetes by using a GWAS approach. GNPDA2 is an enzyme involved in the hexosamine biosynthesis pathway, which is known to be important for nutrient sensing in various organism. Its counter enzyme, GFAT, has previously been shown to be important to the development of insulin resistance in diabetes. The implication of GNPDA2 and GFAT in metabolism is scarce and the effect of both enzymes over appetite and glucose homeostasis is unknown.Aim: Identify the role of GNPDA2 and GFAT in nutrient sensing circuits of the CNS that are important for the regulation of both appetite and glucose homeostasis.Methods: Using Long Evans rats, we administered either a GNPDA2 or GFAT antagonist or vehicle in i3vt.Key Findings: GNPDA2 is highly expressed in hypothalamus and adipose tissue, followed by muscle and liver. GNPDA2 is expressed in different hypothalamic nuclei (ARC, DMH, LHA, PVN). GNPDA2 is downregulated in hypothalamus under diet-induced obesity (as previously described), but GFAT expression does not change. Moreover, i3vt infusion of GNPDA2 or GFAT inhibitor resulted in increased c-Fos in areas related to appetite and glucose homeostasis control as PVN and DMH and to a lesser extent in the LHA and ARC. Central inhibition of GNPDA2 does not alter either acute food intake or body weight; however, GFAT inhibition diminished appetite and body weight due to visceral illness. In addition, central administration of the GNPDA2 antagonist, prior to an intraperitoneal glucose tolerance test, resulted in glucose intolerance in comparison to vehicle without altering insulin levels.Significance: These results suggest that central GNPDA2 does not control appetite, but regulates glucose homeostasis.
Highlights
A growing body of evidence points to an important role of the central nervous system (CNS), in particular the hypothalamus, to regulate energy balance and glucose homeostasis
To start understanding the role of central glucosamine-6-phosphate deaminase 2 (GNPDA2) in appetite and glucose homeostasis control, we analyzed GNPDA2 expression in different nuclei of the hypothalamus (ARC, PVN, DMH and LHA) that regulate both roles, and we found that the transcript is expressed in all of them (Figure 1B)
Once we identified that GNPDA2 is expressed in hypothalamus and its expression is controlled by nutrients, we decided to identify the anatomical location of neurons in the hypothalamus, activated by either glutamine-fructose-6-phosphate aminotransferase (GFAT) and GNPDA2 inhibitors, that might be implicated in appetite control and glucose homeostasis
Summary
A growing body of evidence points to an important role of the central nervous system (CNS), in particular the hypothalamus, to regulate energy balance and glucose homeostasis. The hypothalamus can sense and integrate peripheral signals such as hormones and nutrients and make responses to maintain both energy and glucose homeostasis [1]. Acute central glucosamine infusion has been demonstrated to augment the feeding response during low glucose levels [3]. Infusing glucosamine into the third ventricle of the hypothalamus (i3vt) produces glucose intolerance [4], demonstrating the importance of this pathway in glucose homeostasis. Bypassing the GFAT step by administration of glucosamine provokes insulin resistance in 3T3-L1 cell line [7]
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