Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of ...chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murine Gpr1 mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) and Cmklr1, Gpr1 expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygous Gpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lacking Gpr1 exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects of Gpr1 deficiency on adiposity, energy balance, and glucose homeostasis in vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.
Obesity and diabetes are associated with increased chronic low-grade inflammation and elevated plasma glucose levels. Although inflammation in the fat and liver are established features of ...obesity-associated insulin resistance, the intestine is emerging as a new site for immunologic changes that affect whole-body metabolism. Specifically, microbial and dietary factors incurred by diet-induced obesity influence underlying innate and adaptive responses of the intestinal immune system. These responses affect the maintenance of the intestinal barrier, systemic inflammation, and glucose metabolism. In this Review we propose that an understanding of the changes to the intestinal immune system, and how these changes influence systemic immunity and glucose metabolism in a whole-body integrative and a neuronal-dependent network, will unveil novel intestinal pathologic and therapeutic targets for diabetes and obesity.
The gut microbiota alters energy homeostasis. In parallel, metformin regulates upper small intestinal sodium glucose cotransporter-1 (SGLT1), but whether changes of the microbiota or SGLT1-dependent ...pathways in the upper small intestine mediate metformin action is unknown. Here we report that upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower glucose production in rodents. High-fat diet (HFD) feeding reduces glucose sensing and SGLT1 expression in the upper small intestine. Upper small intestinal metformin treatment restores SGLT1 expression and glucose sensing while shifting the upper small intestinal microbiota partly by increasing the abundance of Lactobacillus. Transplantation of upper small intestinal microbiota from metformin-treated HFD rats to the upper small intestine of untreated HFD rats also increases the upper small intestinal abundance of Lactobacillus and glucose sensing via an upregulation of SGLT1 expression. Thus, we demonstrate that metformin alters upper small intestinal microbiota and impacts a glucose-SGLT1-sensing glucoregulatory pathway.
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•Upper small intestinal glucose sensing activates SGLT1 to lower glucose production•High-fat diet reduces glucose-SGLT1 sensing and decreases Lactobacillus•Metformin restores glucose-SGLT1 sensing while increasing Lactobacillus•Metformin-treated microbiota transplants restore glucose-SGLT1 sensing
Bauer et al. identify a glucose-sensing pathway in the upper small intestine that lowers glucose production in rodents. A high-fat diet shifts the upper small intestinal microbiota and compromises glucose sensing, while metformin treatment in the upper small intestine counteracts the microbiota shift and restores glucose sensing.
The metabolic role of vagal afferent innervation Waise, T M Zaved; Dranse, Helen J; Lam, Tony K T
Nature reviews. Gastroenterology & hepatology,
10/2018, Letnik:
15, Številka:
10
Journal Article
Recenzirano
The regulation of energy and glucose balance contributes to whole-body metabolic homeostasis, and such metabolic regulation is disrupted in obesity and diabetes. Metabolic homeostasis is orchestrated ...partly in response to nutrient and vagal-dependent gut-initiated functions. Specifically, the sensory and motor fibres of the vagus nerve transmit intestinal signals to the central nervous system and exert biological and physiological responses. In the past decade, the understanding of the regulation of vagal afferent signals and of the associated metabolic effect on whole-body energy and glucose balance has progressed. This Review highlights the contributions made to the understanding of the vagal afferent system and examines the integrative role of the vagal afferent in gastrointestinal regulation of appetite and glucose homeostasis. Investigating the integrative and metabolic role of vagal afferent signalling represents a potential strategy to discover novel therapeutic targets to restore energy and glucose balance in diabetes and obesity.
Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small ...intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway.
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•Upper small intestinal fatty acid-ACSL3 sensing impacts glucose homeostasis•HFD decreases Lactobacillus gasseri (LG) and disrupts ACSL3-fatty acid sensing•Regular chow microbiota transplant restores LG and ACSL3-lipid sensing•Lactobacillus gasseri administration restores ACSL3-lipid sensing in HFD rodents
Bauer et al. report that a glucoregulatory pre-absorptive ACSL3-dependent fatty acid-sensing pathway in the upper small intestine is compromised by a high-fat diet. Fatty acid sensing and glucose homeostasis are restored by probiotic Lactobacillus gasseri administration or by transplantation of microbiota from chow-fed animals.
Chemerin is an adipose-derived hormone that regulates immunity and energy homesotasis. To date, all known chemerin functions have been attributed to activation of the G protein-coupled receptor ...chemokine-like receptor-1 (CMKLR1). Chemerin is also the only known ligand for a second receptor, G protein-coupled receptor-1 (GPR1), whose signaling and function remains unknown. This study investigated the in vitro signal transduction mechanisms of CMKLR1 and GPR1 using a panel of luciferase-reporters and pathway-specific inhibitors. Herein we report the novel finding that chemerin signals through a RhoA and rho-associated protein kinase (ROCK)-dependent pathway for activation of the transcriptional regulator serum-response factor (SRF). Despite similarities in RhoA/ROCK, Gαi/o, and MAPK signaling, we also demonstrate species-specific and receptor-dependent variations in GPR1 and CMKLR1 signaling and expression of the SRF target genes EGR1, FOS and VCL. Moreover, we demonstrate that signaling through p38, Gαi/o, RhoA, and ROCK is required for chemerin-mediated chemotaxis of L1.2 lymphocytes and AGS gastric adenocarcinoma cells. These results provide, to our knowledge, the first empirical evidence that GPR1 is a functional chemerin receptor and identify RhoA/SRF as a novel chemerin-signaling axis via both CMKLR1 and GPR1.
•GPR1 is an active signaling receptor for chemerin.•CMKLR1 and GPR1 signal through RhoA and ROCK.•Chemerin signaling increases serum-response factor activation (SRF).•Chemerin activation of CMKLR1 and GPR1 enhances LPA-mediated RhoA signaling.•Chemerin-mediated chemotaxis requires RhoA/ROCK, MAPK, and Gαi/o signaling.
Bone is a dynamic tissue that is continuously remodeled through the action of formative osteoblasts and resorptive osteoclasts. Chemerin is a secreted protein that activates chemokine-like receptor 1 ...(CMKLR1), a G protein-coupled receptor expressed by various cell types including adipocytes, osteoblasts, mesenchymal stem cells (MSCs), and macrophages. Previously, we identified chemerin as a regulator of adipocyte and osteoblast differentiation of MSCs. Herein we examined the role of chemerin in Lin(-) Sca1(+) c-kit(+) CD34(+) hematopoietic stem cell (HSC) osteoclastogenesis. We found that HSCs expressed both chemerin and CMKLR1 mRNA and secreted chemerin protein into the extracellular media. Neutralization of chemerin with a blocking antibody beginning prior to inducing osteoclast differentiation resulted in a near complete loss of osteoclastogenesis as evidenced by reduced marker gene expression and matrix resorption. This effect was conserved in an independent model of RAW264.7 cell osteoclastogenesis. Reintroduction of chemerin by reversal of neutralization rescued osteoclast differentiation indicating that chemerin signaling is essential to permit HSC differentiation into osteoclasts but following blockade the cells maintained the potential to differentiate into osteoclasts. Mechanistically, neutralization of chemerin blunted the early receptor activator of nuclear factor-kappa B ligand induction of nuclear factor of activated T-cells 2 (NFAT2), Fos, Itgb3, and Src associated with preosteoclast formation. Consistent with a central role for NFAT2, induction or activation of NFAT2 by forced expression or stimulation of intracellular calcium release rescued the impairment of HSC osteoclastogenesis caused by chemerin neutralization. Taken together, these data support a novel autocrine/paracrine role for chemerin in regulating osteoclast differentiation of HSCs through modulating intracellular calcium and NFAT2 expression/activation.
High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. Here we show that acute administration of ...casein hydrolysate directly into the upper small intestine increases glucose tolerance and inhibits glucose production in rats, independently of changes in plasma amino acids, insulin levels, and food intake. Inhibition of upper small intestinal peptide transporter 1 (PepT1), the primary oligopeptide transporter in the small intestine, reverses the preabsorptive ability of upper small intestinal casein infusion to increase glucose tolerance and suppress glucose production. The glucoregulatory role of PepT1 in the upper small intestine of healthy rats is further demonstrated by glucose homeostasis disruption following high protein feeding when PepT1 is inhibited. PepT1-mediated protein-sensing mechanisms also improve glucose homeostasis in models of early-onset insulin resistance and obesity. We demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by PepT1 have beneficial effects on whole-body glucose homeostasis.
Obesity is associated with white adipose tissue (WAT) remodelling characterized by changes in cellular composition, size, and adipokine secretion. Levels of the adipokine chemerin are positively ...associated with obesity; however, the biological function of chemerin in WAT is poorly understood. We identified factors involved in WAT remodelling, including matrix metalloproteinase (Mmp)3 and chemokines (Ccl2, 3, 5, 7), as novel targets of chemerin signalling in mature adipocytes. Inhibition of chemerin signalling increased MMP activity and the recruitment of macrophages towards adipocyte-conditioned media. These effects were mediated through increases in NFkB signalling, suggesting that chemerin exerts an anti-inflammatory influence. We also demonstrate that multiple chemerin isoforms are present in adipocyte-conditioned media and that adipocyte-secreted chemerin, but not synthetic chemerin, recapitulates the activity of endogenous chemerin. Considered altogether, this suggests that endogenously secreted chemerin plays an autocrine/paracrine role in WAT, identifying chemerin as a therapeutic target to modulate adipose remodelling.
•Mature adipocytes express high levels of chemerin and its receptor CMKLR1.•Inhibition of chemerin in mature adipocytes increases MMP3 and chemokine activity.•Effects are mediated through NFkB suggesting chemerin plays anti-inflammatory role.•Adipocyte-secreted chemerin is uniquely-processed.
Retinoic acid (RA) plays important roles in development, growth, and homeostasis through regulation of the nuclear receptors for RA (RARs). Herein, we identify Hypermethylated in Cancer 1 (Hic1) as ...an RA-inducible gene. HIC1 encodes a tumor suppressor, which is often silenced by promoter hypermethylation in cancer. Treatment of cells with an RAR agonist causes a rapid recruitment of an RAR/RXR complex consisting of TDG, the lysine acetyltransferase CBP, and TET 1/2 to the Hic1 promoter. Complex binding coincides with a transient accumulation of 5fC/5caC and concomitant upregulation of Hic1 expression, both of which are TDG dependent. Furthermore, conditional deletion of Tdg in vivo is associated with Hic1 silencing and DNA hypermethylation of the Hic1 promoter. These findings suggest that the catalytic and scaffolding activities of TDG are essential for RA-dependent gene expression and provide important insights into the mechanisms underlying targeting of TET-TDG complexes.
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•The gene Hypermethylated in Cancer 1 (Hic1) is a direct retinoic acid receptor (RAR) target•RA-dependent induction of HIC1 requires a TDG-containing demethylation complex•Deletion of TDG in vivo leads to DNA hypermethylation and loss of HIC1 expression•RAR signaling has a fundamental role in initiating DNA demethylation at select loci
Hassan et al. report that DNA methylation and expression of Hypermethylated in Cancer 1 (Hic1) are regulated by the retinoic acid receptor (RAR) in a TDG dependent manner. Failure to recruit TDG and TETs may contribute to aberrant silencing of HIC1 in cancer.
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