Colonic morphology and function change significantly during ontogenesis. In mammals, many colonic physiological functions are temporally controlled by the circadian clock in the colon, which is entrained by the central circadian clock in the suprachiasmatic nuclei (SCN). The aim of this present study was to ascertain when and how the circadian clock in the colon develops during the perinatal period and whether maternal cues and/or the developing pup SCN may influence the ontogenesis of the colonic clock. Daily profiles of clock genes Per1, Per2, Cry1, Cry2, Rev-erbα, Bmal1, and Clock expression in the colon underwent significant modifications since embryonic day 20 (E20) through postnatal days (P) 2, 10, 20, and 30 via changes in the mutual phasing among the individual clock gene expression rhythms, their relative phasing to the light-dark regime, and their amplitudes. An adult-like state was achieved around P20. The foster study revealed that during the prenatal period, the maternal circadian phase may partially modulate development of the colonic clock. Postnatally, the absence and/or presence of rhythmic maternal care affected the phasing of the clock gene expression profiles in pups at P10 and P20. A reversal in the colonic clock phase between P10 and P20 occurred in the absence of rhythmic signals from the pup SCN. The data demonstrate ontogenetic maturation of the colonic clock and stress the importance of prenatal and postnatal maternal rhythmic signals for its development. These data may contribute to the understanding of colonic function-related diseases in newborn children.
Introduction: Solute Carrier (SLC) and ATP-binding cassette (ABC) transporters expressed in the intestine, liver, and kidney determine the absorption, distribution, and excretion of drugs. In addition, most molecular and cellular processes show circadian rhythmicity controlled by circadian clocks that leads to diurnal variations in the pharmacokinetics and pharmacodynamics of many drugs and affects their therapeutic efficacy and toxicity. Area covered: This review provides an overview of the current knowledge on the circadian rhythmicity of drug transporters and the molecular mechanisms of their circadian control. Evidence for coupling drug transporters to circadian oscillators and the plausible candidates conveying circadian clock signals to target drug transporters, particularly transcription factors operating as the output of clock genes, is discussed. Expert opinion: The circadian machinery has been demonstrated to interact with the uptake and efflux of various drug transporters. The evidence supports the concept that diurnal changes that affect drug transporters may influence the pharmacokinetics of the drugs. However, more systematic studies are required to better define the timing of pharmacologically important drug transporter regulation and determine tissue- and sex-dependent differences. Finally, the transfer of knowledge based on the results and conclusions obtained primarily from animal models will require careful validation before it is applied to humans.
We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery. We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls. Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before RYGB were lower than in lean individuals, but substantially upregulated 6 months post-RYGB. Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.
Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects against obesity-induced systemic disease in mice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularly well to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generating enzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.
Obesity is associated with extensive expansion and remodeling of the adipose tissue architecture, including its microenvironment and extracellular matrix (ECM). Although obesity has been reported to induce adipose tissue fibrosis, the composition of the ECM under healthy physiological conditions has remained underexplored and debated. Here, we used a combination of three established techniques (picrosirius red staining, a colorimetric hydroxyproline assay, and sensitive gene expression measurements) to evaluate the status of the ECM in metabolically healthy lean (MHL) and metabolically unhealthy obese (MUO) subjects. We investigated ECM deposition in the two major human adipose tissues, namely the omental and subcutaneous depots. Biopsies were obtained from the same anatomic region of respective individuals. We found robust ECM deposition in MHL subjects, which correlated with high expression of collagens and enzymes involved in ECM remodeling. In contrast, MUO individuals showed lower expression of ECM components but elevated levels of ECM cross-linking and adhesion proteins, e.g., lysyl oxidase and thrombospondin. Our data suggests that subcutaneous fat is more prone to express proteins involved in ECM remodeling than omental adipose tissues. We conclude that a more dynamic ability to deposit and remodel ECM may be a key signature of healthy adipose tissue, and that subcutaneous fat may adapt more readily to changing metabolic conditions than omental fat.
Introduction: Solute Carrier (SLC) and ATP-binding cassette (ABC) transporters expressed in the intestine, liver, and kidney determine the absorption, distribution, and excretion of drugs. In addition, most molecular and cellular processes show circadian rhythmicity controlled by circadian clocks that leads to diurnal variations in the pharmacokinetics and pharmacodynamics of many drugs and affects their therapeutic efficacy and toxicity.Area covered: This review provides an overview of the current knowledge on the circadian rhythmicity of drug transporters and the molecular mechanisms of their circadian control. Evidence for coupling drug transporters to circadian oscillators and the plausible candidates conveying circadian clock signals to target drug transporters, particularly transcription factors operating as the output of clock genes, is discussed.Expert opinion: The circadian machinery has been demonstrated to interact with the uptake and efflux of various drug transporters. The evidence supports the concept that diurnal changes that affect drug transporters may influence the pharmacokinetics of the drugs. However, more systematic studies are required to better define the timing of pharmacologically important drug transporter regulation and determine tissue- and sex-dependent differences. Finally, the transfer of knowledge based on the results and conclusions obtained primarily from animal models will require careful validation before it is applied to humans.
Study Objective Obesity is a predisposing factor for cardiometabolic and kidney disease. Inflammation has been identified as an underlying risk factor. However, studies report conflicting results on the impact of short‐ and long‐term weight loss on obesity‐related inflammation. Here we investigate levels of inflammation in lean, metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) patients, and the impact of short‐ and long‐term weight loss, using multiplex arrays and bioinformatics analysis. Methods Obese patients scheduled to undergo gastric bypass surgery were age‐ and sex‐matched to lean controls (ClinicalTrials.gov NCT02322073), and sub‐classified as metabolically healthy (MHO: n=4) or unhealthy (MUO: n=7) using International Diabetes Guidelines (i.e. metabolically unhealthy is defined as having more than two cardiometabolic risk factors: central adiposity, hyperglycemia, elevated triglycerides, decrease HDL‐cholesterol, elevated blood pressure). Gender was not a part off inclusion/exclusion criteria, thus three patients were male and eight were female. Plasma was collected at baseline and following short‐ and long‐term weight loss. The short‐term weight loss consisted of a 3‐week diet regime, which takes place before surgery and resulted in 8.7 kg weight loss. The long‐term weight loss was measured 1‐year post‐surgery, at which time the patients had lost on average 46.7 kg. A multiplex array of 96 inflammation‐related plasma proteins (Olink Inflammation Panel) was analyzed using R‐studio program software version 1.1.38 and Graph Pad Prism. Results Inflammation (measured as C‐reactive protein) was higher in both MHO and MUO patients than in lean controls, although multivariate analysis of the multiplex array identified 11 proteins that were significantly different between the MHO/MUO groups at baseline. Hierarchal cluster analysis further revealed that the MHO group clustered together at baseline and after short‐term dieting, but not after long‐term weight loss. Both MHO and MUO groups presented with higher levels of macrophage inflammatory protein (MIP)‐1α, C‐C motif chemokine (CCL)‐4, oncostatin‐M and TNSF‐14, as compared to lean controls. CCL‐4 was not affected by weight loss, but oncostatin‐M and TNSF‐14 were significantly lowered by long‐term weight loss in both obese groups. MIP‐1α was further elevated by short‐term dieting, but reduced following long‐term weight loss. IL‐8 and CDCP1 were only increased in the MUO group, while IL‐18 and the anti‐inflammatory LAP TGF‐β1 were only increased in the MHO group; none of these proteins were attenuated by weight loss. Surprisingly, CCL25 and Fractalkine (chemotactics for T‐cells and monocytes) were not elevated in MHO or MUO groups at baseline compared to lean controls, but they were significantly higher 1‐year post‐surgery. Conclusion In summary, our study revealed that although obesity increases inflammatory markers, these may be differently regulated in MHO versus MUO patients and by short‐ and long‐term weight loss. Currently ongoing investigations are delineating the specific pathways involved. Support or Funding Information The Borgeson lab is supported by the Knut & Alice Wallenberg Foundation, Wallenberg Centre for Molecular & Translational Medicine, the Swedish Research Council, (no. 2016/82), the Swedish Society for Medical Research (no. S150086), Ake Wiberg's Foundation (no. M15‐0058), Konrad & Helfrid Johansson's foundation. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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