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Objective. Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise intervention and oral hypoglycaemic drug of metformin (MET) alone or combined on hepatic lipid accumulation. To investigate if oxidative stress and endoplasmic reticulum stress (ERS) are involved in lipotoxicity-induced hepatocyte apoptosis in diabetic mice and whether exercise and/or MET alleviated oxidative stress or ERS-apoptosis by AMPK-Nrf2-HO-1 signaling pathway. Methods. Forty db/db mice with diabetes ( random blood glucose ≥ 250 mg / dL ) were randomly allocated into four groups: control (CON), exercise training alone (EX), metformin treatment alone (MET), and exercise combined with metformin (EM) groups. Hematoxylin-eosin and oil red O staining were carried out to observe hepatic lipid accumulation. Immunohistochemical and TUNEL methods were used to detect the protein expression of the binding immunoglobulin protein (BiP) and superoxide dismutase-1 (SOD1) and the apoptosis level of hepatocytes. ERS-related gene expression and the AMPK-Nrf2-HO-1 signaling pathway were tested by western blotting. Results. Our data showed that db/db mice exhibited increased liver lipid accumulation, which induced oxidative and ER stress of the PERK-eIF2α-ATF4 pathway, and hepatocyte apoptosis. MET combined with exercise training significantly alleviated hepatic lipid accumulation by suppressing BiP expression, the central regulator of ER homeostasis, and its downstream PERK-eIF2α-ATF4 pathway, as well as upregulated the AMPK-Nrf2-HO-1 signaling pathway. Moreover, the combination of exercise and MET displayed protective effects on hepatocyte apoptosis by downregulating Bax expression and TUNEL-positive staining, restoring the balance of cleaved-caspase-3 and caspase-3, and improving the antioxidant defense system to prevent oxidative damage in db/db mice. Conclusion. Compared to MET or exercise intervention alone, the combined exercise and metformin exhibited significant effect on ameliorating hepatic steatosis, inhibiting oxidative and ER stress-induced hepatocyte apoptosis via improving the capacity of the antioxidant defense system and suppression of the PERK-eIF2α-ATF4 pathway. Furthermore, upregulation of AMPK-Nrf2-HO-1 signaling pathway might be a key crosstalk between MET and exercise, which may have additive effects on alleviating hepatic lipid accumulation.

Human survival relies on an adequate oxygen (O2) supply. Hemoglobin (Hb) is the main carrier of O2 in the circulatory system and its levels directly affect tissue oxygenation. When O2 levels decrease, a state of hypoxia occurs. Under hypoxia, a systemic response mechanism activates, increasing O2 supply and decreasing O2 demand. The response is regulated by the hypoxia-inducible factor (HIF) which targets genes in various pathways including energy metabolism. HIF is governed by O2-dependent HIF prolyl 4‐hydroxylases (HIF-P4Hs 1‐3), and inhibitors of these enzymes are currently used to treat renal anemia. Lower serum cholesterol levels have been reported in patients receiving HIF-P4H inhibitors. To study the roles of each HIF-P4H isoenzyme in metabolism, we used two pan HIF-P4H inhibitors in wild-type (WT) and HIF-P4H deficient mice. Both inhibitors improved the metabolic profile of WT mice in a dose-dependent and safe manner. HIF-P4H-1 loss lowered body weight and cholesterol levels upon aging while HIF-P4H-3 loss led to an adverse metabolic profile. HIF-P4H-2 deficiency promoted metabolic health, protecting from non-alcoholic fatty liver disease via increased browning of white adipose tissue (WAT) and consequent thermogenesis, and by enhanced fructose metabolism in the intestine. Regulation of HIF target mRNAs was isoenzyme-specific, very few requiring inhibition by all three isoenzymes. Using the normal variation in Hb levels as a surrogate measure for hypoxia, we explored how Hb levels relate to metabolic health in mice and humans, and used Mendelian randomization (MR) to evaluate causality. Lower Hb levels associated with a healthier metabolic profile and higher Hb levels with an adverse one. Additionally, higher Hb levels associated with development of type 2 diabetes, an increased risk for liver fat accumulation and with both total and cardiovascular-related mortalities. Moreover, expression of key HIF target genes associated with lower systolic blood pressure in MR analyses and healthier body composition in mice. Lastly, venesection altered Hb levels and metabolic parameters in mice. The results present selective inhibition of isoenzyme 2, or 1/2, as a novel therapeutic option for metabolic diseases. Additionally, low-end normal Hb levels present as metabolically favorable, whereas high Hb levels increase the risk for developing metabolic diseases. Tiivistelmä Ihmisen elämä on riippuvainen riittävästä hapensaannista. Hemoglobiini (Hb) on verenkiertoelimistön ensisijainen hapenkuljettaja ja sen pitoisuus vaikuttaa suoraan kudosten hapettumiseen. Kun happipitoisuus laskee, vallitsee hypoksia. Hypoksia aktivoi elimistössä vastemekanismin lisäten hapen kuljetusta ja vähentäen kulutusta. Vastetta säätelee hypoksiassa indusoituva tekijä (HIF), säädellen kohdegeenejä useilla biologisilla reiteillä, mukaan lukien energia-aineenvaihdunta. Happiriippuvaiset HIF-prolyyli-4-hydroksylaasit (HIF-P4H-1‐3), joiden estäjiä käytetään munuaisperäisen anemian hoitoon, säätelevät HIF:ää. HIF-P4H estäjää saaneilla potilailla on raportoitu matalampia seerumin kolesteroliarvoja. Tutkiaksemme HIF-P4H isoentsyymien vaikutuksia aineenvaihdunnassa, käytimme kahta HIF-P4H estäjää villityypin (VT) ja HIF-P4H-puutteisilla hiirillä. Estäjät olivat turvallisia ja paransivat VT hiirten metabolista profiilia annosriippuvaisesti. Ikääntyessä HIF-P4H-1 puutos alensi painoa ja kolesterolitasoja, kun taas HIF-P4H-3 puutos johti epäsuotuisaan metaboliaan. HIF-P4H-2 vaje paransi metabolista terveyttä, suojaten hiiriä ei-alkoholiperäiseltä rasvamaksalta lisääntyneiden valkean rasvan ruskettumisesta johtuvan lämmöntuoton ja suoliston fruktoosimetabolian johdosta. HIF kohdegeenien lähetti-RNA tasojen säätely oli isoentsyymikohtaista ja vain muutamia säädeltiin kaikkien kolmen estolla. Käyttäen Hb:n normaalivaihtelua hypoksian mittarina ja Mendeliaanista randomisaatiota (MR) kausaliteetin arviointiin, tutkimme Hb tasojen vaikutusta metaboliaan. Matalat Hb tasot assosioituivat suotuisaan ja korkeat epäsuotuisaan metaboliseen profiiliin. Lisäksi korkeat Hb tasot assosioituivat tyypin 2 diabeteksen kehittymiseen, lisääntyneeseen maksan rasvoittumisriskiin ja kokonais- sekä sydän- ja verisuonisairausperäiseen kuolleisuuteen. Lisäksi keskeisten HIF-kohdegeenien ilmentyminen assosioitui matalampaan systoliseen verenpaineeseen MR analyyseissä ja terveempään kehonkoostumukseen hiirillä. Verenluovutus vaikutti hiirten Hb tasoihin ja metabolisiin muuttujiin. Töissä saadut tulokset esittävät erityisesti isoentsyymi 2, tai 1/2 selektiivisen HIF-P4H eston, uutena mahdollisena hoitovaihtoehtona metabolisille sairauksille. Lisäksi matalat normaalivaihteluvälin Hb tasot esiintyvät metabolisesti suotuisina ja korkeat lisäävät metabolisten sairauksien kehittymisriskiä.

Exercise and diet are treatments for nonalcoholic fatty liver disease (NAFLD) and prediabetes, however, how exercise and diet interventions impact gut microbiota in patients is incompletely understood. We previously reported a 8.6-month, four-arm (Aerobic exercise, n = 29; Diet, n = 28; Aerobic exercise + Diet, n = 29; No intervention, n = 29) randomized, singe blinded (for researchers), and controlled intervention in patients with NAFLD and prediabetes to assess the effect of interventions on the primary outcomes of liver fat content and glucose metabolism. Here we report the third primary outcome of the trial—gut microbiota composition—in participants who completed the trial (22 in Aerobic exercise, 22 in Diet, 23 in Aerobic exercise + Diet, 18 in No Intervention). We show that combined aerobic exercise and diet intervention are associated with diversified and stabilized keystone taxa, while exercise and diet interventions alone increase network connectivity and robustness between taxa. No adverse effects were observed with the interventions. In addition, in exploratory ad-hoc analyses we find that not all subjects responded to the intervention in a similar manner, when using differentially altered gut microbe amplicon sequence variants abundance to classify the responders and low/non-responders. A personalized gut microbial network at baseline could predict the individual responses in liver fat to exercise intervention. Our findings suggest an avenue for developing personalized intervention strategies for treatment of NAFLD based on host-gut microbiome ecosystem interactions, however, future studies with large sample size are needed to validate these discoveries. The Trial Registration Number is ISRCTN 42622771.

We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms associated with these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12 weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.

This study investigated the impact of Nordic walking on bone properties in postmenopausal women with pre-diabetes and non-alcohol fatty liver disease (NAFLD). A total of 63 eligible women randomly participated in the Nordic walking training (AEx, n = 33), or maintained their daily lifestyle (Con, n = 30) during intervention. Bone mineral content (BMC) and density (BMD) of whole body (WB), total femur (TF), femoral neck (FN), and lumbar spine (L2-4) were assessed by dual-energy X-ray absorptiometry. Serum osteocalcin, pentosidine, receptor activator of nuclear factor kappa-B ligand (RANKL) levels were analyzed by ELISA assay. After an 8.6-month intervention, the AEx group maintained their BMCTF, BMDTF, BMCL2−4, and BMDL2−4, and increased their BMCFN (p = 0.016), while the Con group decreased their BMCTF (p = 0.008), BMDTF (p = 0.001), and BMDL2−4 (p = 0.002). However, no significant group × time interaction was observed, except for BMDL2−4 (p = 0.013). Decreased pentosidine was correlated with increased BMCWB(r = −0.352, p = 0.019). The intervention has no significant effect on osteocalcin and RANKL. Changing of bone mass was associated with changing of pentosidine, but not with osteocalcin and RANKL. Our results suggest that Nordic walking is effective in preventing bone loss among postmenopausal women with pre-diabetes and NAFLD.