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Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

Adipose tissue-resident macrophages (ATMs) are reported to be important for maintaining adipose tissue remodeling and homeostasis. ATMs were classified for the first time in 2007 into the M1 and M2 types. This theory suggests that in the non-obese adipose tissue, the anti-inflammatory, alternatively activated macrophages (AAMs) predominate, and regulate tissue homeostasis, remodeling, and insulin sensitivity. On the other hand, classically activated M1-type macrophages increase rapidly in obesity, secrete inflammatory cytokines, such as TNFα and IL-6, and induce insulin resistance. In recent years, experimental findings that cannot be explained by this theory have been clarified one after another and the theory is being reconsidered. In this review, based on recent findings, we summarize reports on the novel metabolic regulatory functions of ATMs beyond the M1/M2 paradigm.

Aims/Introduction: Endogenous insulin secretion could be recovered by improving hyperglycemia in patients with type 2 diabetes. This study aimed to investigate the association between short‐term recovery of insulin secretion during hospitalization and clinical background or future glycemic control in patients with type 2 diabetes. Materials and Methods: A total of 127 patients with type 2 diabetes were included. The recovery of endogenous insulin secretion was determined using the following indices: index A: fasting C‐peptide index (CPI) at discharge – fasting CPI on admission; index B: postprandial CPI at discharge – postprandial CPI on admission; and index C: Δ C‐peptide immunoreactivity (CPR) (postprandial CPR − fasting CPR) at discharge – ΔCPR on admission. We examined the associations of each index with clinical background and future glycemic control measured by glycosylated hemoglobin and continuous glucose monitoring. Results: Using index A and B, the age was significantly younger, whereas BMI and visceral fat area were significantly higher in the high‐recovery group than in the low‐recovery group. Changes in glycosylated hemoglobin levels were significantly greater at 6 and 12 months in the high‐recovery group in the analysis of index C. The receiver operating characteristic curve analysis identified the index B and index C as indicators to predict glycosylated hemoglobin <7.0% at 6 months after discharge. Furthermore, index C was positively correlated with the time in the target glucose range, and inversely correlated with the standard deviation of glucose at 3 and 12 months after discharge. Conclusions: Short‐term recovery of insulin secretion in response to a meal during hospitalization, evaluated with the index‐C, might predict future glycemic control. [ABSTRACT FROM AUTHOR]

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-p, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective., Introduction There is a worldwide epidemic of obesity, type 2 diabetes, and metabolic syndrome (1, 2). Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome and is [...]

Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity- resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic- induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential., Introduction Gut microbiota affect the host's energy balance, glucose and lipid metabolism, and the immune response (1). Obesity, type 2 diabetes, and metabolic syndrome are all associated with changes in [...]

Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206+ M2-like macrophages and FAPs during the recovery process using a transgenic mouse model. Depletion of CD206+ M2-like macrophages or deletion of CD206+ M2-like macrophages-specific TGF-β1 gene induces myogenesis and muscle regeneration. We show that depletion of CD206+ M2-like macrophages activates FAPs and activated FAPs secrete follistatin, a promyogenic factor, thereby boosting the recovery process. Conversely, deletion of the FAP-specific follistatin gene results in impaired muscle stem cell function, enhanced fibrosis, and delayed muscle regeneration. Mechanistically, CD206+ M2-like macrophages inhibit the secretion of FAP-derived follistatin via TGF-β signaling. Here we show that CD206+ M2-like macrophages constitute a microenvironment for FAPs and may regulate the myogenic potential of muscle stem/satellite cells. Muscle regeneration requires the contribution and communication of various different cell types. Here, Nawaz et al. show that CD206+ macrophages inhibit the secretion of the promyogenic factor follistatin by fibro-adipogenic progenitor cells, impeding myogenesis and muscle regeneration. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD. Monosodium glutamate (MSG) mice, which exhibited obesity and insulin resistance, were treated with SRT1720, a specific SIRT1 activator from the age of 6-16 wk. Sixteen-week-old MSG mice exhibited increased liver triglyceride content and elevated levels of aminotransferase. SRT1720 treatment significantly reduced these levels without affecting body weight or food intake. These results suggested that the administration of SRT1720 ameliorated the development of NAFLD in MSG mice. The expressions of lipogenic genes, such as sterol regulatory element-binding protein-lc, acetyl-CoA carboxylase, and fatty acid synthase, and the serum lipid profiles, including free fatty acids, were elevated in MSG mice and were reduced by SRT1720 treatment. SRT1720 treatment also reduced the expressions of lipogenic genes in cultured HepG2 cells. Furthermore, SRT 1720 treatment decreased the expressions of marker genes for oxidative stress and inflammatory cytokines in the liver of MSG mice. Taken together, SRT1720 treatment may reduce liver lipid accumulation, at least in part, by directly reducing the expressions of lipogenic genes. The reduction of oxidative stress and inflammation may also be involved in the amelioration of NAFLD. nonalcoholic fatty liver disease; lipogenesis; [beta]-oxidation; monosodium glutamate doi: 10.1152/ajpendo.90997.2008.