Renal olfactory receptor 1393 contributes to the progression of type 2 diabetes in a diet-induced obesity model

Abstract

Olfactory receptors (ORs) are G protein‐coupled receptors which serve to detect odorants in the nose. It is now appreciated that these receptors have roles beyond odorant detection and serve important functions in a number of different tissues. Included in the list of ectopic ORs is olfactory receptor 1393 (Olfr1393). We recently found (Shepard, et al Sci Rep 2016) that Olfr1393 is a novel regulator of sodium glucose co‐transporter 1 (Sglt1) surface expression in the renal proximal tubule. Olfr1393 is localized to the apical membrane of the proximal tubule and knockout (KO) mice present with mild glycosuria and improved glucose tolerance despite euglycemia and normal insulin levels. The Sglts have emerged as therapeutic targets for patients with type II diabetes, and these inhibitors have been shown to attenuate the progression of diabetic nephropathy including restoring glomerular filtration rate (GFR) through increased distal sodium delivery. Given Olfr1393's role as a regulator of Sglt1 in the proximal tubule, we hypothesized that the absence of Olfr1393 may attenuate the progression of diabetes and hyperfiltration. To examine this, Olfr1393 WT (n= 7) and KO (n=12) mice were challenged with a high fat diet (60% kcal) for 16 weeks to induce early stage diabetes. As expected, Olfr1393 WT mice displayed significant weight gain and impaired glucose tolerance. GFR (as measured via the transcutaneous detection of FITC‐Sinistrin clearance) was measured after 0, 11.5, and 16 weeks on the diet and, as expected, WT mice developed glomerular hyperfiltration by 16 weeks (μl/min GFR: week 0 – 187.3±16.4; week 16 – 401.0±17.0). Conversely, high fat diet‐fed KO mice exhibited a significant improvement in glucose tolerance (Area under the curve in thousands: WT – 43.0±6.4; KO – 27.9±2.6, p=0.02) and a blunted hyperfiltration (μl/min GFR: week 0 – 170.7±13.6; week 16 – 312.7±25.1; week 16 WT vs KO p=0.02). Collectively, this data indicates that renal Olfr1393 can contribute to the progression of type II diabetes, likely as a regulator of Sglt1. Support or Funding Information NIDDK This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

“…The down-regulation of these chaperones results in the functional plasma membrane expression of ΔF508 CFTR (49). Outside of the OSNs, ORs are found to be ectopically expressed in tissues as diverse as heart, gut, and testis (50,51). These ectopic ORs are unlikely to need RTPs to be functionally expressed in many of these nonolfactory tissues where no or very low RTP1 and RTP2 expressions are detected.…”

“…We looked at the nature of the 66 positions in a set of 4 mouse and 19 human ORs detected ectopically (SI Appendix, Fig. S7) (50,51). The 66 positions are not significantly more conserved in ectopic ORs than all mouse ORs (38 out of the 66 sites, P = 0.398, Wilcoxon signed rank test).…”

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

“…The downregulation of these chaperones results in the functional plasma membrane expression of ΔF508 CFTR (48). Outside of the olfactory sensory neurons, ORs are found to be ectopically expressed in tissues as diverse as heart, gut, and testis (49,50). These ectopic ORs are unlikely to need RTPs to be functionally expressed in many of these non-olfactory tissues where no or very low RTP1 and RTP2 expressions are detected.…”

“…We looked at the nature of the 66 positions in a set of four mouse and nineteen human ORs detected ectopically ( Fig. S7) (49,50). The 66 positions are not significantly more conserved in ectopic ORs than all mouse ORs (38 out of the 66 sites, p=0.398, Wilcoxon signed rank test).…”

The Sensing Liver: Localization and Ligands for Hepatic Murine Olfactory and Taste Receptors

“…While the physiological relevance of these receptors is continuing to emerge, many of these ‘extra sensory’ localizations have been linked to physiological and pathophysiological functions ( Spehr et al, 2003 ; Neuhaus et al, 2009 ; Sharma et al, 2017 ; Abaffy et al, 2018 ; Massberg and Hatt, 2018 ; Lee et al, 2019 ; Tole et al, 2019 ). Work from our laboratory has focused on the characterization of renal OR Olfr1393 and its role in glucose handling ( Shepard et al, 2016 , 2019 ) and diabetes ( Shepard et al, 2019 ). ORs have also been shown to function in the regulation of adiposity, blood pressure, and carcinoma proliferation ( Pluznick et al, 2013 ; Massberg et al, 2015 ; Wu et al, 2015 ).…”