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Bitter Taste Receptors and Α-Gustducin Regulate the Secretion of Ghrelin with Functional Effects on Food Intake and Gastric Emptying

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Bitter taste receptors and α-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying Sara Janssen, Jorien Laermans, Pieter-Jan Verhulst, Theo Thijs, Jan Tack, and Inge Depoortere1 Department of Pathophysiology, Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, 3000 Leuven, Belgium Edited by Roger D. Cone, Vanderbilt University School of Medicine, Nashville, TN, and approved December 28, 2010 (received for review August 4, 2010) Ghrelin is a hunger hormone with gastroprokinetic properties but which may in turn initiate a hormonal or neural cascade pathway the factors controlling ghrelin secretion from the stomach are (11). Taste receptors are also present in the tongue epithelium unknown. Bitter taste receptors (T2R) and the gustatory G and consist of two G protein-coupled receptor families, T1R and proteins, α-gustducin (gust) and α-transducin, are expressed in T2R. Subtypes of the T1R family heterodimerize to detect sweet the gut and are involved in the chemosensation of nutrients. This (T1R2+T1R3) and L-amino acid tastants (T1R1+T1R3), whereas study aimed to investigate whether T2R-agonists affect (i) ghrelin the T2R receptor family can detect bitter and consists of more release via α-gustducin and (ii) food intake and gastric emptying than 30 diverse members. Gustducin is the α subunit of a trimeric via the release of ghrelin. The mouse stomach contains two ghrelin G-protein complex that is involved in sweet, bitter, and umami cell populations: cells containing octanoyl and desoctanoyl ghrelin, taste transduction (12, 13). Not all bitter-sensitive taste cells con- α α which were colocalized with -gustducin and -transducin, and tain α-gustducin, indicating the existence of other G-protein cells staining for desoctanoyl ghrelin. Gavage of T2R-agonists in- α-subunits in bitter taste transduction, such as α-transducin and creased plasma octanoyl ghrelin levels in WT mice but the effect −/− Gi (14). was partially blunted in gust mice. Intragastric administration Gustducin-coupled sweet taste receptors have been demon- of T2R-agonists increased food intake during the first 30 min in WT −/− strated in endocrine cells in the proximal intestine of mice and but not in gust and ghrelin receptor knockout mice. This in- humans (15, 16). In mice, α-gustducin was frequently found in L- crease was accompanied by an increase in the mRNA expression MEDICAL SCIENCES type cells (GLP-1) but rarely in K cells (GIP) cells. These cells of agouti-related peptide in the hypothalamus of WT but not of − − fail to release GLP-1 in response to glucose within the gut lumen gust / mice. The temporary increase in food intake was followed in α-gustducin knockout mice (15). The presence of multiple by a prolonged decrease (next 4 h), which correlated with an in- fi hibition of gastric emptying. The delay in emptying, which was transcripts corresponding to speci c bitter taste receptors has partially counteracted by ghrelin, was not mediated by cholecys- been demonstrated in the upper GI tract of rodents and in a tokinin and GLP-1 but involved a direct inhibitory effect of T2R- mouse GI enteroendocrine cell line, STC-1 (17). It has been agonists on gastric contractility. This study is unique in providing reported that the bitter agonists, phenylthiocarbamide (PTC) functional evidence that activation of bitter taste receptors stim- and denatonium benzoate (DB), induce the release of chole- ulates ghrelin secretion. Modulation of endogenous ghrelin levels cystokinin (CCK) and GLP-1 from STC-1 cells (11, 18). by tastants may provide novel therapeutic applications for the This study aimed to investigate whether the ghrelin cell is treatment of weight -and gastrointestinal motility disorders. colocalized with the G proteins of the gustatory complex, α- gustducin and α-transducin, and whether bitter taste receptors nutrient sensing | gastrointestinal peptides | appetite coupled to α-gustducin could function as chemosensors for the ghrelin cell. We therefore investigated the effect of bitter taste- fi receptor agonists on the release of ghrelin in WT and α-gustducin hrelin is a 28-amino acid peptide with an octanoyl modi - −/− Gcation at Ser3, which is mainly produced by the “X/A-like” knockout (gust ) mice and determined the functional con- cells of the oxyntic glands of the stomach (1) in response to sequences of the altered ghrelin secretion with respect to food conditions of negative energy balance. The octanoylated form of intake and gastric emptying. ghrelin is the biological active form, although it represents less Results than 20% of the circulating ghrelin. Ghrelin signals through the ghrelin receptor, previously known as the growth hormone se- Colocalization of Ghrelin with G Proteins of the Gustatory Complex. fl cretagogue receptor (GHS-R), to stimulate food intake and to Immuno uorescence studies provided evidence for the existence decrease fat utilization to stimulate body weight gain (2). Malik of two ghrelin cell populations (Fig. 1). The total ghrelin cell et al. (3) showed that even in the absence of caloric deficiency, population was identified with an antibody, which did not dis- ghrelin may favor food consumption by enhancing the hedonic criminate between octanoyl and desoctanoyl ghrelin (Fig. 1A). Of and incentive responses to food-related cues. Ghrelin also has this total ghrelin cell population, 66 ± 3% of the cells costained for important effects on gastrointestinal (GI) motility, which may octanoyl ghrelin (Fig. 1A) and 100% were colocalized with des- contribute to appetite signaling. It induces strong “hunger” con- octanoyl ghrelin (Fig. 1B). These findings suggest that the octa- tractions in the fasted state, originating in the stomach and mi- noyl ghrelin cell population was also colocalized with desoctanoyl grating distally, and accelerates gastric emptying in man and ghrelin and that there was a second ghrelin cell population that rodents (4–7). Plasma ghrelin levels peak before a meal and de- contained only desoctanoyl ghrelin. crease shortly after food consumption in humans to dictate the timing of the meals (8). The magnitude of the decrease in plasma ghrelin levels is dependent on the caloric content (9) and the Author contributions: J.T. and I.D. designed research; S.J., J.L., P.-J.V., and T.T. performed macronutrient composition of the meal (10), but the factors in- research; S.J., J.L., and T.T. analyzed data; and S.J. wrote the paper. volved in chemosensation of the ghrelin cell are unknown. The authors declare no conflict of interest. The recent identification of taste receptors and their down- This article is a PNAS Direct Submission. stream signaling molecules in the GI mucosa suggests a role for 1To whom correspondence should be addressed. E-mail: [email protected]. these receptors in the functional detection of nutrients in the gut, be. www.pnas.org/cgi/doi/10.1073/pnas.1011508108 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 300 3500 AB* *** 250 3000 * * 200 2500 * A 2000 150 1500 100 1000 50 (pg/ml) ghrelin Total 500 Octanoyl ghrelin (pg/ml) 0 0 02030405060 0 2030405060 Time aer gavage (min) Time aer gavage (min) 160 ** 3000 CD140 ** 2500 *** *** 120 ** ** 100 2000 80 1500 60 1000 40 20 (pg/ml) ghrelin Total 500 fi Octanoyl ghrelin (pg/ml) Fig. 1. Identi cation of ghrelin cell populations. Colocalization between 0 0 total (octanoyl+desoctanoyl) ghrelin (red) and (A) octanoyl ghrelin (green) control DB PTC PTU salicin quinine control DB PTC PTU salicin quinine or (B) desoctanoyl ghrelin (green) in sections of the mouse stomach. (Scale bars, 20 μm.) EF# 160 *** 3000 140 2500 *** *** 120 α-Gustducin–positive cells were visualized in the brush cells 100 2000 A 80 1500 (Fig. 2 ), in the region of the limiting ridge, the boundary be- 60 1000 B 40 tween fundus and corpus, and in some endocrine cells (Fig. 2 ). 500 20 (pg/ml) ghrelin Total α – Octanoyl ghrelin (pg/ml) In contrast, -transducin positive cells were only found in endo- 0 0 crine cells (Fig. 2C). No colocalization was observed between WT gust-/- WT gust-/- control bier mixture control bier mixture ghrelin and α-gustducin found in the brush cells, although sev- eral ghrelin-positive cells were found in close proximity to the Fig. 3. (A and B) Time-dependent increase in plasma octanoyl ghrelin and α-gustducin–positive cells (Fig. 2A). In contrast, ghrelin was co- total ghrelin levels in response to oral gavage of T2R-agonists in WT mice (n =4–6). (C and D) Comparison of the effect of gavage of individual T2R localized with G proteins of the gustatory complex present in en- agonists on octanoyl ghrelin and total ghrelin secretion (n =6–8). (E and F) docrine cells. Almost 61 ± 12% of the α-gustducin–positive and Octanoyl and total plasma ghrelin levels after gavage of T2R-agonists (40 − − 98 ± 2% of the α-transducin–positive endocrine cells colocalized min) in WT (n =18–21) and gust / (n =18–19) mice. *P < 0.05, **P < 0.01, # −/− with ghrelin. The ghrelin cell population that contained octanoyl ***P < 0.001 vs. control; P < 0.05 WT vs. gust . and desoctanoyl ghrelin colocalized for 88 ± 2% with α-gustducin B ± α C (Fig. 2 ) and for 85 2% with -transducin (Fig. 2 ). For the cell Effect of Bitter Taste-Receptor Agonists on Plasma Ghrelin Secretion. population that contained only desoctanoyl ghrelin, it was difficult Gavage of a mixture of bitter agonists in WT mice increased to discern whether these cells colocalized with any of the gustatory plasma concentrations of octanoyl (P < 0.05) and total (P < 0.001) G proteins because staining for desoctanoyl ghrelin also stained ghrelin in a time-dependent manner (Fig. 3 A and B). Both the cells for octanoyl ghrelin. octanoyl ghrelin and total ghrelin levels peaked 40 min after ga- vage (octanoyl ghrelin: t0:72± 7 pg/mL vs.
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  • Cellular Insulin Resistance Disrupts Hypothalamic Mhypoa-POMC/GFP Neuronal Signaling Pathways

    Cellular Insulin Resistance Disrupts Hypothalamic Mhypoa-POMC/GFP Neuronal Signaling Pathways

    A NAZARIANS-ARMAVIL and others Insulin resistance in novel 220:1 13–24 Research POMC/GFP cell lines Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways Anaies Nazarians-Armavil1, Jennifer A Chalmers1, Claire B Lee1, Wenqing Ye1 and Denise D Belsham1,2,3,4 Correspondence Departments of 1Physiology, 2Obstetrics and Gynaecology and 3Medicine, University of Toronto, Medical Sciences should be addressed Building 3344, 1 Kings College Circle, Toronto, Ontario, Canada M5S 1A8 to D D Belsham 4Division of Cellular and Molecular Biology, Toronto Genera Hospital Research Institute, University Health Network, Email Toronto, Ontario, Canada M5S 1A8 [email protected] Abstract POMC neurons play a central role in the maintenance of whole-body energy homeostasis. Key Words This balance requires proper regulation of POMC neurons by metabolic hormones, such as " proopiomelanocortin insulin. However, the heterogeneous cellular population of the intact hypothalamus " a-melanocortin-synthesizing presents challenges for examining the molecular mechanisms underlying the potent hormone anorexigenic effects of POMC neurons, and there is currently a complete lack of mature " insulin POMC neuronal cell models for study. To this end, we have generated novel, immortalized, " neuroendocrinology adult-derived POMC-expressing/a-MSH-secreting cell models, mHypoA-POMC/GFP lines 1–4, " insulin resistance representing the fluorescence-activated cell-sorted POMC population from primary POMC- " cell biology " hypothalamus Journal of Endocrinology eGFP mouse hypothalamus. The presence of Pomc mRNA in these cell lines was confirmed, and a-MSH was detected via immunofluorescence. a-MSH secretion in the mHypoA- POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay.