Featured ArticlesVolume 5 | No. 4 | April 2016
|Insulin-like peptide 5 is a microbially regulated peptideInsulin-like peptide (INSL) 5 is a member of the relaxin/insulin family, which comprises insulin, insulin-like growth factor 1 and 2, relaxin 1 and 2, and INSL3-7, and has been recently identified in colonic and brain tissue. Lee and colleagues show that colonic expression of Insl5 is regulated by microbiota and energy availability. Their findings suggest that INSL5 is a new hormone that promotes hepatic glucose production, although its effect is mild. INSL5 may act as a sensor of energy and modulator of homeostatic glucose production under conditions of energy deprivation.|
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Objective: Insulin-like peptide 5 (INSL5) is a recently identified gut hormone that is produced predominantly by L-cells in the colon, but its function is unclear. We have previously shown that colonic expression of the gene for the L-cell hormone GLP-1 is high in mice that lack a microbiota and thus have energy-deprived colonocytes. Our aim was to investigate if energy deficiency also affected colonic Insl5 expression and to identify a potential role of INSL5.
Methods: We analyzed colonic Insl5 expression in germ-free (GF), conventionally raised (CONV-R), conventionalized (CONV-D) and antibiotic-treated mice, and also assessed the effect of dietary changes on colonic Insl5 expression. In addition, we characterized the metabolic phenotype of Insl5-/- mice.
Results: We showed that colonic Insl5 expression was higher in GF and antibiotic-treated mice than in CONV-R mice, whereas Insl5 expression in the brain was higher in CONV-R versus GF mice. We also observed that colonic Insl5 expression was suppressed by increasing the energy supply in GF mice by colonization or high-fat feeding. We did not observe any differences in food intake, gut transit or oral glucose tolerance between Insl5-/- and wild-type mice. However, we showed impaired intraperitoneal glucose tolerance in Insl5-/- mice. We also observed improved insulin tolerance and reduced hepatic glucose production in Insl5-/- mice.
Conclusions: We have shown that colonic Insl5 expression is regulated by the gut microbiota and energy availability. We propose that INSL5 is a hormone that could play a role in promoting hepatic glucose production during periods of energy deprivation.[Hide abstract]
|Essential role of UCP1 modulating the central effects of thyroid hormonesThyroid hormones control important biological processes, including metabolism and energy balance. Alvarez-Crespo and colleagues investigate the role of brown adipose tissue and uncoupling protein 1 (UCP1) on the thermogenic effects of central triiodothyronine (T3)-treatment. They find that the entire thermogenic effect of central T3-treatment is dependent upon the presence of UCP1. Additionally, further metabolic effects, such as T3-induced hyperphagia, are also entirely UCP1-dependent. The possible significance of these observations on the understanding of T3 effects is evident, and this pathway may additionally be involved in the mediation of broad metabolic effects of other centrally acting agents.|
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Objective: Classically, metabolic effects of thyroid hormones (THs) have been considered to be peripherally mediated, i.e. different tissues in the body respond directly to thyroid hormones with an increased metabolism. An alternative view is that the metabolic effects are centrally regulated. We have examined here the degree to which prolonged, centrally infused triiodothyronine (T3) could in itself induce total body metabolic effects and the degree to which brown adipose tissue (BAT) thermogenesis was essential for such effects, by examining uncoupling protein 1 (UCP1) KO mice.
Methods: Wildtype and UPC1 KO mice were centrally-treated with T3 by using minipumps. Metabolic measurements were analyzed by indirect calorimetry and expression analysis by RT-PCR or western blot. BAT morphology and histology were studied by immunohistochemistry.
Results: We found that central T3-treatment led to reduced levels of hypothalamic AMP-activated protein kinase (AMPK) and elevated body temperature (0.7 °C). UCP1 was essential for the T3-induced increased rate of energy expenditure, which was only observable at thermoneutrality and notably only during the active phase, for the increased body weight loss, for the increased hypothalamic levels of neuropeptide Y (NPY) and agouti-related peptide (AgRP) and for the increased food intake induced by central T3-treatment. Prolonged central T3-treatment also led to recruitment of BAT and britening/beiging (“browning”) of inguinal white adipose tissue (iWAT).
Conclusions: We conclude that UCP1 is essential for mediation of the central effects of thyroid hormones on energy balance, and we suggest that similar UCP1-dependent effects may underlie central energy balance effects of other agents.[Hide abstract]
|Mitochondrial gene polymorphisms aggravate diet-induced non-alcoholic steatohepatitisIn contrast to simple hepatic steatosis, the incidence of non-alcoholic steatohepatitis (NASH) substantially increases the risk for hepatic diseases as well as cardiovascular complications and overall mortality. Schröder and colleagues provide evidence that mitochondrial genetics impact hepatic mitochondrial function and that following alterations, such as generation of reactive oxygen species and induction of TNFα signaling, act as a first hit within the pathology of NASH. They demonstrate that environmental stress is required, as a second hit, to cause the full picture of NASH.|
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Objective: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH.
Methods: To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mtAFVB/N mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8).
Results: At baseline conditions, C57BL/6J-mtAFVB/N mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mtAFVB/N mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells.
Conclusions: We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH.[Hide abstract]
|Alterations in hypothalamic gene expression following Roux-en-Y gastric bypassBariatric surgery procedures, including Roux-en-Y gastric bypass (RYGB), are considered the most effective treatment of obesity and its co-morbidities. Barkholt et al. show that arcuate levels of orexigenic neuropeptide Y and agouti-related peptide mRNAs are significantly upregulated in RYGB rats indicating that classical hunger signalling pathways are activated. In contrast, second order downstream orexigenic signals in the lateral hypothalamic area (melanin-concentrating hormone neurons) are blunted in RYGB rats suggesting that the hunger-signals arising from the arcuate nucleus do not translate into sensations of hunger nor into food-seeking behavior.|
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Objective: The role of the central nervous system in mediating metabolic effects of Roux-en-Y gastric bypass (RYGB) surgery is poorly understood. Using a rat model of RYGB, we aimed to identify changes in gene expression of key hypothalamic neuropeptides known to be involved in the regulation of energy balance.
Methods: Lean male Sprague-Dawley rats underwent either RYGB or sham surgery. Body weight and food intake were monitored bi-weekly for 60 days post-surgery. in situ hybridization mRNA analysis of hypothalamic AgRP, NPY, CART, POMC and MCH was applied to RYGB and sham animals and compared with ad libitum fed and food-restricted rats. Furthermore, in situ hybridization mRNA analysis of dopaminergic transmission markers (TH and DAT) was applied in the midbrain.
Results: RYGB surgery significantly reduced body weight and intake of a highly palatable diet but increased chow consumption compared with sham operated controls. In the arcuate nucleus, RYGB surgery increased mRNA levels of orexigenic AgRP and NPY, whereas no change was observed in anorexigenic CART and POMC mRNA levels. A similar pattern was seen in food-restricted versus ad libitum fed rats. In contrast to a significant increase of orexigenic MCH mRNA levels in food-restricted animals, RYGB did not change MCH expression in the lateral hypothalamus. In the VTA, RYGB surgery induced a reduction in mRNA levels of TH and DAT, whereas no changes were observed in the substantia nigra relative to sham surgery.
Conclusions: RYGB surgery increases the mRNA levels of hunger-associated signaling markers in the rat arcuate nucleus without concomitantly increasing downstream MCH expression in the lateral hypothalamus, suggesting that RYGB surgery puts a brake on orexigenic hypothalamic output signals. In addition, down-regulation of midbrain TH and DAT expression suggests that altered dopaminergic activity also contributes to the reduced intake of palatable food in RYGB rats.[Hide abstract]
|Granulocyte colony-stimulating factor (G-CSF): a saturated fatty acid-induced myokine with insulin-desensitizing propertiesOrdelheide et al. investigate free fatty acids (FFAs)-induced CSF3 expression, the underlying molecular mechanism(s), and G-CSF’s functions in human myotubes and adipocytes. In addition, they aim to translate the metabolic G-CSF effects shown in vitro to humans in vivo by testing the impact of CSF3 tagging single nucleotide polymorphisms on human metabolic traits. Their data point to G-CSF as a novel insulin-desensitizing myokine of relevance for human insulin sensitivity and glucose tolerance.|
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Objective: Circulating long-chain free fatty acids (FFAs) are important metabolic signals that acutely enhance fatty acid oxidation, thermogenesis, energy expenditure, and insulin secretion. However, if chronically elevated, they provoke inflammation, insulin resistance, and β-cell failure. Moreover, FFAs act via multiple signaling pathways as very potent regulators of gene expression. In human skeletal muscle cells differentiated in vitro (myotubes), we have shown in previous studies that the expression of CSF3, the gene encoding granulocyte colony-stimulating factor (G-CSF), is markedly induced upon FFA treatment and exercise.
Methods and results: We now report that CSF3 is induced in human myotubes by saturated, but not unsaturated, FFAs via Toll-like receptor 4-dependent and -independent pathways including activation of Rel-A, AP-1, C/EBPα, Src, and stress kinases. Furthermore, we show that human adipocytes and myotubes treated with G-CSF become insulin-resistant. In line with this, a functional polymorphism in the CSF3 gene affects adipose tissue- and whole-body insulin sensitivity and glucose tolerance in human subjects with elevated plasma FFA concentrations.
Conclusion: G-CSF emerges as a new player in FFA-induced insulin resistance and thus may be of interest as a target for prevention and treatment of type 2 diabetes.[Hide abstract]