Taste receptor type 1 member 3 is required for the fertility of male mice.

Male infertility is a global health concern. However, its underlying pathophysiology remains unclear. Taste receptor type 1 member 3 (TAS1R3) is highly expressed in the testes, indicating its potential involvement in male fertility. Using wild-type and Tas1r3 knockout (KO) mice, we investigated whether TAS1R3 modulates male reproductive function. Tas1r3 KO mice exhibited reduced male fertility compared to WT mice, with fewer live pups per litter and a delayed first litter. Testicular transcriptome analysis indicated suppressed PKA/CREB/StAR signaling-mediated testosterone synthesis in Tas1r3 KO mice. In silico single-cell RNA sequencing revealed considerably higher Tas1r3 expression in Leydig cells than in other testicular cell subtypes. An in vitro study validated that Tas1r3 knockdown downregulated the expression of Creb1 and steroidogenic genes in Leydig cells. Our results suggest that testicular TAS1R3 is intricately involved in male reproduction via the PKA/CREB/StAR signaling pathway, highlighting its potential as a promising target for addressing male infertility.

Taste receptor type 1 member 3 regulates Western diet-induced male infertility.

Western diet (WD), characterized by a high intake of fats and sugary drinks, is a risk factor for male reproductive impairment. However, the molecular mechanisms underlying this remain unclear. Taste receptor type 1 member 3 (TAS1R3), activated by ligands of WD, is highly expressed in extra-oral tissues, particularly in the testes. Here, we investigated to determine the effects of WD intake on male reproduction and whether TAS1R3 mediates WD-induced impairment in male reproduction. Male C57BL/6 J wild-type (WT) and Tas1r3 knockout (KO) mice were fed either a normal diet and plain water (ND) or a 60 % high-fat-diet and 30 % (w/v) sucrose water (WD) for 18 weeks (n = 7-9/group). Long-term WD consumption significantly impaired sperm count, motility and testicular morphology in WT mice with marked Tas1r3 overexpression, whereas Tas1r3 KO mice were protected from WD-induced reproductive impairment. Testicular transcriptome analysis revealed downregulated AMP-activated protein kinase (AMPK) signaling and significantly elevated AMPK-targeted nuclear receptor 4A1 (Nr4a1) expression in WD-fed Tas1r3 KO mice. In vitro studies further validated that Tas1r3 knockdown in Leydig cells prevented the suppression of Nr4a1 and downstream steroidogenic genes (Star, Cyp11a1, Cyp17a1, and Hsd3b1) caused by high glucose, fructose, and palmitic acid levels, and maintained the levels of testosterone. Additionally, we analyzed the public human dataset to assess the clinical implications of our findings and confirmed a significant association between TAS1R3 and male-infertility-related diseases. Our findings suggest that TAS1R3 regulates WD-induced male reproductive impairment via the AMPK/NR4A1 signaling and can be a novel therapeutic target for male infertility.

Taste receptor type 1 member 3 enables western diet-induced anxiety in mice.

BACKGROUND: Accumulating evidence supports that the Western diet (WD), a diet high in saturated fat and sugary drinks, contributes to the pathogenesis of anxiety disorders, which are the most prevalent mental disorders worldwide. However, the underlying mechanisms by which WD causes anxiety remain unclear. Abundant expression of taste receptor type 1 member 3 (TAS1R3) has been identified in the hypothalamus, a key brain area involved in sensing peripheral nutritional signals and regulating anxiety. Thus, we investigated the influence of excessive WD intake on anxiety and mechanisms by which WD intake affects anxiety development using wild-type (WT) and Tas1r3 deficient (Tas1r3-/-) mice fed a normal diet (ND) or WD for 12 weeks. RESULTS: WD increased anxiety in male WT mice, whereas male Tas1r3-/- mice were protected from WD-induced anxiety, as assessed by open field (OF), elevated plus maze (EPM), light-dark box (LDB), and novelty-suppressed feeding (NSF) tests. Analyzing the hypothalamic transcriptome of WD-fed WT and Tas1r3-/- mice, we found 1,432 genes significantly up- or down-regulated as a result of Tas1r3 deficiency. Furthermore, bioinformatic analysis revealed that the CREB/BDNF signaling-mediated maintenance of neuronal regeneration, which can prevent anxiety development, was enhanced in WD-fed Tas1r3-/- mice compared with WD-fed WT mice. Additionally, in vitro studies further confirmed that Tas1r3 knockdown prevents the suppression of Creb1 and of CREB-mediated BDNF expression caused by high levels of glucose, fructose, and palmitic acid in hypothalamic neuronal cells. CONCLUSIONS: Our results imply that TAS1R3 may play a key role in WD-induced alterations in hypothalamic functions, and that inhibition of TAS1R3 overactivation in the hypothalamus could offer therapeutic targets to alleviate the effects of WD on anxiety.

Taste receptor type 1 member 3 mediates diet-induced cognitive impairment in mice.

AIMS: Long-term consumption of a western diet (WD), which is characterized by high intake of saturated fats and sugary drinks, causes cognitive impairment. However, the molecular mechanism by which WD induces cognitive impairment remains unclear. Taste receptor type 1 member 3 (TAS1R3), activated by ligands of WD, is expressed in extra-oral tissues, including the brain, and particularly in the hippocampus. This study investigated whether TAS1R3 regulates WD-induced cognitive impairment in mice. MAIN METHODS: Male C57BL/6J wild-type (WT) and Tas1r3 knock-out (KO) mice were fed either a normal diet (ND) or WD for 18 weeks. Cognitive functions were assessed using novel object recognition and Barnes maze tests. The mechanisms underlying WD-induced cognitive impairment were assessed using RNA-sequencing and bioinformatics analysis. KEY FINDINGS: Cognitive impairment was observed in WT mice fed WD (WT-WD) compared with WT-ND mice. Conversely, mice lacking TAS1R3 were not cognitively impaired even under long-term WD feeding. Hippocampal transcriptome analysis revealed upregulated AMP-activated protein kinase (AMPK) signaling and increased AMPK-targeted sirtuin 3 expression in KO-WD mice. Pathway enrichment analysis showed that response to oxidative stress was downregulated, whereas neurogenesis was upregulated in dentate gyrus of KO-WD mice. In vitro studies validated the findings, indicating that Tas1r3 knockdown directly upregulated decreased sirtuin 3 expression, its downstream genes-related to oxidative stress, and apoptosis induced by WD condition in hippocampal neuron cells. SIGNIFICANCE: TAS1R3 acts as a critical mediator of WD-induced cognitive impairment in mice, thereby offering potential as a novel therapeutic target to prevent WD-induced cognitive impairment.

Gut taste receptor type 1 member 3 is an intrinsic regulator of Western diet-induced intestinal inflammation.

BACKGROUND: Long-term intake of a Western diet (WD), characterized by a high-fat content and sugary drinks, is hypothesized to contribute to the development of inflammatory bowel disease (IBD). Despite the identified clinical association, the molecular mechanisms by which dietary changes contribute to IBD development remain unknown. Therefore, we examined the influence of long-term intake of a WD on intestinal inflammation and the mechanisms by which WD intake affects IBD development. METHODS: Mice fed normal diet or WD for 10 weeks, and bowel inflammation was evaluated through pathohistological and infiltrated inflammatory cell assessments. To understand the role of intestinal taste receptor type 1 member 3 (TAS1R3) in WD-induced intestinal inflammation, cultured enteroendocrine cells harboring TAS1R3, subjected to RNA interference or antagonist treatment, and Tas1r3-deficient mice were used. RNA-sequencing, flow cytometry, 16S metagenomic sequencing, and bioinformatics analyses were performed to examine the involved mechanisms. To demonstrate their clinical relevance, intestinal biopsies from patients with IBD and mice with dextran sulfate sodium-induced colitis were analyzed. RESULTS: Our study revealed for the first time that intestinal TAS1R3 is a critical mediator of WD-induced intestinal inflammation. WD-fed mice showed marked TAS1R3 overexpression with hallmarks of serious bowel inflammation. Conversely, mice lacking TAS1R3 failed to exhibit inflammatory responses to WD. Mechanistically, intestinal transcriptome analysis revealed that Tas1r3 deficiency suppressed mTOR signaling, significantly increasing the expression of PPARγ (a major mucosal defense enhancer) and upregulating the expression of PPARγ target-gene (tight junction protein and antimicrobial peptide). The gut microbiota of Tas1r3-deficient mice showed expansion of butyrate-producing Clostridia. Moreover, an increased expression of host PPARγ-signaling pathway proteins was positively correlated with butyrate-producing microbes, suggesting that intestinal TAS1R3 regulates the relationship between host metabolism and gut microflora in response to dietary factors. In cultured intestinal cells, regulation of the TAS1R3-mTOR-PPARγ axis was critical for triggering an inflammatory response via proinflammatory cytokine production and secretion. Abnormal regulation of the axis was observed in patients with IBD. CONCLUSIONS: Our findings suggest that the TAS1R3-mTOR-PPARγ axis in the gut links Western diet consumption with intestinal inflammation and is a potential therapeutic target for IBD.