ObjectivePeroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD).DesignWe constructed a novel hepatocyte-specific PPARα knockout (Pparαhep−/−) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing.ResultsHepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparαhep−/− mice when compared with Pparα−/− mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα−/− mice became overweight during ageing while Pparαhep−/− remained lean. However, like Pparα−/− mice, Pparαhep−/− fed a standard diet developed hepatic steatosis in ageing.ConclusionsAltogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.

is often recommended as a preventive measure for women with recurrent cystitis, but supportive data are sparse. OBJECTIVE To assess the efficacy of increased daily water intake on the frequency of recurrent cystitis in premenopausal women. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, controlled, 12-month trial at a clinical research center (years 2013-2016). Among 163 healthy women with recurrent cystitis (Ն3 episodes in past year) drinking less than 1.5 L of fluid daily assessed for eligibility, 23 were excluded and 140 assigned to water or control group. Assessments of daily fluid intake, urinary hydration, and cystitis symptoms were performed at baseline, 6-and 12-month visits, and monthly telephone calls. INTERVENTIONS Participants were randomly assigned to drink, in addition to their usual fluid intake, 1.5 L of water daily (water group) or no additional fluids (control group) for 12 months. MAIN OUTCOMES AND MEASURES Primary outcome measure was frequency of recurrent cystitis over 12 months. Secondary outcomes were number of antimicrobial regimens used, mean time interval between cystitis episodes, and 24-hour urinary hydration measurements. RESULTS The mean (SD) age of the 140 participants was 35.7 (8.4) years, and the mean (SD) number of cystitis episodes in the previous year was 3.3 (0.6). During the 12-month study period, the mean (SD) number of cystitis episodes was 1.7 (95% CI, 1.5-1.8) in the water group compared with 3.2 (95% CI, 3.0-3.4) in the control group, with a difference in means of 1.5 (95% CI, 1.2-1.8; P < .001). Overall, there were 327 cystitis episodes, 111 in the water group and 216 in the control group. The mean number of antimicrobial regimens used to treat cystitis episodes was 1.9 (95% CI, 1.7-2.2) and 3.6 (95% CI, 3.3-4.0), respectively, with a difference in means of 1.7 (95% CI, 1.3-2.1; P < .001). The mean time interval between cystitis episodes was 142.8 (95% CI, 127.4-160.1) and 84.4 (95% CI, 75.4-94.5) days, respectively, with a difference in means of 58.4 (95% CI, 39.4-77.4; P < .001). Between baseline and 12 months, participants in the water group, compared with those in the control group, had increased mean (SD) urine volume (1.4 [0.04] vs 0.1 [0.04] L; P < .001) and voids (2.4 [0.2] vs −0.1 [0.2]; P < .001) and decreased urine osmolality (−402.8 [19.6] vs −24.0 [19.5] mOsm/kg; P < .001). CONCLUSIONS AND RELEVANCE Increased water intake is an effective antimicrobial-sparing strategy to prevent recurrent cystitis in premenopausal women at high risk for recurrence who drink low volumes of fluid daily. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02444975

SummaryWhile the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp−/− mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp−/− mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21.

In the face of urbanisation, surplus energy intake, sedentary habits and obesity, type 2 diabetes has developed into a major health concern worldwide. Commonly overlooked in contemporary obesity research, the liver is emerging as a central regulator of whole body energy homeostasis. Liver-derived proteins known as hepatokines are now considered attractive targets for the development of novel type 2 diabetes treatments. This commentary presents examples of three leading hepatokines: fetuin-A, the first to be described and correlated with increased inflammation and insulin resistance; angiopoietin-like protein (ANGPTL)8/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question; and fibroblast growth factor 21 (FGF21), an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions. Novel discoveries in hepatokine research may lead to promising biomarkers and treatments for metabolic disorders and type 2 diabetes. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).

Purpose An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of optimal hydration. Methods Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, complemented by manual search of article reference lists and the expertise of relevant practitioners for each area studied. Results The available literature suggest the effects of increased water intake on health may be direct, due to increased urine flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease. Conclusion In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5 L day−1 to allow for the daily excretion of 2 to 3 L of dilute (< 500 mOsm kg−1) urine. Simple urinary markers of hydration such as urine color or void frequency may be used to monitor and adjust intake.

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Chronic vasopressin secretion induced by recurrent mild heat stress exposure is significantly enhanced by limited rehydration with a fructose-containing beverage both in rodents and in humans. Moreover, this effect has been associated with upregulation of the polyol–fructokinase pathway and increased renal oxidative stress. Previously, we have shown that pharmacological inhibition of both V1a and V2 vasopressin receptors with conivaptan improved such renal alterations. The aim of this study was to evaluate the independent contributions of V1a and V2 receptors to the renal damage caused by mild heat stress and limited rehydration with a fructose-containing beverage. Osmotic minipumps were used to deliver either relcovaptan (0.64 mg/day) or tolvaptan (0.25 mg/day) in male Wistar rats for two weeks. Corresponding dilution vehicles were used as controls. To induce dehydration, rats were exposed to mild heat stress (37 °C for 1 h, Monday to Friday). All groups received a 10% fructose solution as a rehydration fluid for 2 h after mild heat stress. For the remainder of the day and on weekends, rats received tap water. The independent blockade of either the V1a or the V2 receptor prevented renal damage, reduced oxidative stress, and decreased plasma cortisol and systemic inflammation. However, the beneficial effects were regulated by different mechanisms. Tolvaptan inhibited polyol–fructokinase pathway overactivation, while relcovaptan prevented upregulation of the renin–angiotensin system and SGK1 expression. These data suggest that both V1a and V2 receptors participate in renal damage caused by heat stress-induced dehydration when fructose-containing beverages are used as rehydration fluids.

The human intestinal microbiota has been shown to be modulated during inflammatory conditions. Probiotic administration has been shown to affect the immune system and cytokine expression which can affect inflammation and health outcomes. There seems to be an association between the mother's intestinal microbiota and inflammation biomarkers, both of which may contribute to newborn early life immune and metabolic programming and impact short and long-term health outcomes. Probiotic supplementation during pregnancy has been shown to influence metabolic health, immunity, and gastrointestinal health of the mother, and can also have carry-over benefits to infants such as infant allergy risk reduction. Therefore, this review focuses on the evidence of probiotic administration in women of reproductive age, including during pregnancy and its impact on inflammatory markers and on maternal and infant health. We performed a PubMed search for articles published in English in the last 20 years. Immune markers were narrowed to serum and breast milk levels of TNF-α, IL-6 and TGF-β, IgA, and IL-10. Studies that investigated the beneficial effects of interventions in women with gestational diabetes mellitus, polycystic ovarian syndrome, and infant allergy management are summarized. These results show a beneficial or neutral effect on selected health outcomes and that it is safe for woman and their infants. The effect of probiotics on modulation of inflammatory markers was probiotic specific. More research is needed to further our understanding of the mechanisms underlying the effects of probiotics on inflammation and how these effects improve health outcomes.