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Inhibition of mitochondrial complex I (NADH dehydrogenase) is the primary mechanism of the antidiabetic drug metformin and various unrelated natural toxins. Complex I inhibition can also be induced by antidiabetic PPAR agonists, and it is elicited by methionine restriction, a nutritional intervention causing resistance to diabetes and obesity. Still, a comprehensible explanation to why complex I inhibition exerts antidiabetic properties and engenders metabolic inefficiency is missing. To evaluate this issue, we have systematically reanalyzed published transcriptomic datasets from MPP-treated neurons, metformin-treated hepatocytes, and methionine-restricted rats. We found that pathways leading to NADPH formation were widely induced, together with anabolic fatty acid biosynthesis, the latter appearing highly paradoxical in a state of mitochondrial impairment. However, concomitant induction of catabolic fatty acid oxidation indicated that complex I inhibition created a "futile" cycle of fatty acid synthesis and degradation, which was anatomically distributed between adipose tissue and liver in vivo. Cofactor balance analysis unveiled that such cycling would indeed be energetically futile (-3 ATP per acetyl-CoA), though it would not be redox-futile, as it would convert NADPH into respirable FADH2 without any net production of NADH. We conclude that inhibition of NADH dehydrogenase leads to a metabolic shift from glycolysis and the citric acid cycle (both generating NADH) towards the pentose phosphate pathway, whose product NADPH is translated 1:1 into FADH2 by fatty acid cycling. The diabetes-resistant phenotype following hepatic and intestinal complex I inhibition is attributed to FGF21- and GDF15-dependent fat hunger signaling, which remodels adipose tissue into a glucose-metabolizing organ. [ABSTRACT FROM AUTHOR]

To investigate the effects of dietary methionine restriction (MetR) and endurance exercise on bone quality under a condition of estrogen deficiency, female Sprague-Dawley rats (36-wk-old) were assigned to a sham surgery group or one of five ovariectomized groups subjected to interventions of no treatment (Ovx), endurance exercise (Exe), methionine restriction (MetR), methionine restriction plus endurance exercise (MetR + Exe), and estrogen treatment (Est). Rats in the exercise groups were subjected to a treadmill running regimen. MetR and control diets contained 0.172 and 0.86% methionine, respectively. After the 12-wk intervention, all animals were killed, and serum and bone tissues were collected for analyses. Compared with estrogen treatment, MetR diet and endurance exercise showed better or equivalent efficiency in reducing body weight gain caused by ovariectomy (P < 0.05). Whereas only the Est group showed evidence for reduced bone turnover compared with the Ovx group, MetR diet and/or endurance exercise demonstrated efficiencies in downregulating serum insulin, leptin, triglyceride, and thiobarbituric acid reactive substances (P < 0.05). Both the Exe and MetR groups showed higher femoral cortical and total volumetric bone mineral density (vBMD), but only the Exe and Est groups preserved cancellous bone volume and/or vBMD of distal femora (P < 0.05) compared with the Ovx group. After being normalized to body mass, femora of the MetR and MetR + Exe groups had relatively higher bending strength and dimension values followed by the Sham, Exe, and Est groups (P < 0.05). In conclusion, both MetR diet and endurance exercise improved cortical bone properties, but only endurance exercise preserved cancellous bone under estrogen deficiency. [ABSTRACT FROM AUTHOR]

Dietary methionine restriction (MR) has been suggested to be comparable to endurance exercise with respect to its beneficial effects on health. To further investigate the effects of MR and endurance exercise on growing bone, 7-wk-old male Sprague-Dawley rats were fed different L-methionine (Met)-containing diets with or without endurance exercise intervention (Ex; 0.86% Met, 0.52% Met, 0.17% Met, 0.86% Met-Ex, 0.52% Met-Ex, and 0.17% Met-Ex groups). After an 8-wk intervention period, exercise-trained rats had a 9.2% lower body weight (BW) than did sedentary rats (P < 0.05). Additionally, 0.17% Met-fed rats had 32% lower BW when compared with rats fed the other 2 diets (P < 0.05). Serum osteocalcin was lower in the 0.17% Met-Ex group compared with the other 2 exercise groups and the 0.17% Met group (P < 0.05) . Serum concentrations of C-terminal telopeptide of type 1 collagen were lower in exercise-trained and 0.17% Met-fed rats than in sedentary rats and rats fed the other 2 diets (P < 0.05 for both). Rats fed the 0.17% Met diet had lower trabecular bone volume, bone mineralization activities, and bone mineral content (BMC; e.g., total, cortical, and spongy BMC) and bone mineral density (BMD; e.g., total and spongy BMD) indices compared with rats fed the other 2 diets (P < 0.05). Exercise-trained rats also had lower bonemineralization activity, trabecular osteoclast density, total BMC, cortical BMC, and total BMD compared with sedentary rats (P < 0.05). In total BMD, only the 0.17% Met-Ex group had values lower than the other 2 exercise groups and the 0.17% Met group (P < 0.05). Compared with rats fed the other 2 diets and sedentary rats, the femora of 0.17% Met-fed and exercise-trained rats, respectively, had smaller size and/or lower extrinsic strength but enhanced intrinsic biomechanical properties (P < 0.05). The results indicate that MR and endurance exercise caused lower whole bone mass, size, and/or strength but might enhance intrinsic bone strength. [ABSTRACT FROM AUTHOR]

Dietary methionine restriction (MR) extends lifespan, an effect associated with reduction of body weight gain, and improvement of insulin sensitivity in mice and rats as a result of metabolic adaptations in liver, adipose tissue and skeletal muscle. To test whether MR confers resistance to adiposity and insulin resistance, C57BL/6J mice were fed a high fat diet (HFD) containing either 0.86% methionine (control fed; CF) or 0.12% methionine (methionine-restricted; MR). MR mice on HFD had lower body weight gain despite increased food intake and absorption efficiency compared to their CF counterparts. MR mice on HFD were more glucose tolerant and insulin sensitive with reduced accumulation of hepatic triglycerides. In plasma, MR mice on HFD had higher levels of adiponectin and FGF21 while leptin and IGF-1 levels were reduced. Hepatic gene expression showed the downregulation of Scd1 while Pparg, Atgl, Cd36, Jak2 and Fgf21 were upregulated in MR mice on HFD. Restriction of growth rate in MR mice on HFD was also associated with lower bone mass and increased plasma levels of the collagen degradation marker C-terminal telopeptide of type 1 collagen (CTX-1). It is concluded that MR mice on HFD are metabolically healthy compared to CF mice on HFD but have decreased bone mass. These effects could be associated with the observed increase in FGF21 levels. [ABSTRACT FROM AUTHOR]

The in ovo carcinogenicity assay (IOCA) was used to examine whether the noncarcinogens ε-caprolactam (CAP), D-mannitol (MAN) and nitrosoproline (NPRO) induce toxicity and subsequently morphological changes in embryonic turkey livers compared with the carcinogen diethylnitrosamine (DEN). Various doses of the test compounds were injected into fertilized turkey or quail eggs prior to incubation. Embryonic livers were collected 3–4 days before hatching and processed for histology. The positive control DEN induced hepatocyte altered foci (HAF) and karyomegalic hepatocytes, whereas histological analysis of livers from embryos exposed to CAP, MAN and NPRO did not show such histological changes. The effects of the tested compounds on liver were further examined in hepatocytes cultured from exposed turkey and quail embryos. As observed in ovo, megalocytes as well as karyomegalic hepatocytes were present in hepatocyte cultures established from DEN-exposed turkey embryos, but not from embryos exposed to CAP, MAN or NPRO. It is concluded that CAP, MAN and NPRO do not induce histological changes in embryonic liver of the type produced by the carcinogen DEN, correlating with findings for these compounds in rodent studies. [ABSTRACT FROM AUTHOR]

Some fluoroquinolone antibiotics (FQs) become toxic and mutagenic upon exposure to ultraviolet radiation (UV). Topoisomerase inhibition has been proposed as one possible mechanism involved in this photochemical genotoxicity. To study this reaction, inhibition of the human topoisomerase IIα enzyme by four FQs varying in photochemical genotoxic potency (Bay y3118 [y3118] > Lomefloxacin [Lmx] > Ciprofloxacin [Cpx] > Moxifloxacin [Mox]) was measured in vitro in the presence of UVA irradiation. None of the FQs inhibited topoisomerase IIα in the absence of irradiation. In contrast, with irradiation at 365 nm, the potent photochemically genotoxic y3118 produced strong inhibition of the enzyme by 15% and Cpx caused a weak 5% inhibition, but the more photochemically genotoxic Lmx only showed a transient inhibitory effect at one concentration and one irradiation dose. The photostable Mox had no effect with irradiation. Topoisomerase IIα inhibition by y3118 only occurred when the FQ, DNA, and enzyme were simultaneously present in the UVA-irradiated reaction mixture and was abolished in the absence of ATP, indicating the possible formation of a ternary structure. The y3118 photochemical topoisomerase inhibition correlated with the increased irradiation-mediated binding of radiolabeled FQ to DNA:topoisomerase complexes and was irreversible, like that of the topoisomerase poison, etoposide, without irradiation. The inhibitory effect of photoactivated y3118 on topoisomerase IIα was also observed in the presence of the antioxidant TEMPO, indicating that reactive oxygen species were not involved in the inhibition. These observations demonstrate that some but not all photochemically genotoxic FQs inhibit human topoisomerase IIα, possibly by UV-induced affinity of FQs to DNA:topoisomerase complexes. [ABSTRACT FROM PUBLISHER]