2'-fucosyllactose Supplementation Improves Gut-Brain Signaling and Diet-Induced Obese Phenotype and Changes the Gut Microbiota in High Fat-Fed Mice.

Obesity is characterized by fat accumulation, chronic inflammation and impaired satiety signaling, which may be due in part to gut microbial dysbiosis. Manipulations of the gut microbiota and its metabolites are attractive targets for obesity treatment. The predominant oligosaccharide found in human milk, acts as a prebiotic with beneficial effects on the host. However, little is known about the beneficial effects of 2'-FL in obesity. The aim of this study was to determine the beneficial effects of 2'-FL supplementation on the microbiota-gut-brain axis and the diet-induced obese phenotype in high fat (HF)-fed mice. Male C57/BL6 mice (n = 6/group; six weeks old) were counter-balanced into six weight-matched groups and fed either a low-fat (LF; 10% kcal as fat), HF (45% kcal as fat) or HF diet with 2'-FL (HF_2'-FL) at 1, 2, 5 and 10% (w/v) in drinking water for six weeks. General phenotypes (body weight, energy intake, fat and lean mass), cecal microbiome and metabolites, gut-brain signaling, intestinal permeability and inflammatory and lipid profiles were assessed. Only 10% 2'-FL, but not 1, 2 or 5%, decreased HF diet-induced increases in energy intake, fat mass and body weight gain. A supplementation of 10% 2'-FL changed the composition of cecal microbiota and metabolites compared to LF- and HF-fed mice with an increase in Parabacteroides abundance and lactate and pyruvate, respectively, whose metabolic effects corresponded to our study findings. In particular, 10% 2'-FL significantly reversed the HF diet-induced impairment of cholecystokinin-induced inhibition of food intake. Gene expressions of interleukin (IL)-1β, IL-6, and macrophage chemoattractant protein-1 in the cecum were significantly downregulated by 10% 2'-FL compared to the HF group. Furthermore, 10% 2'-FL suppressed HF diet-induced upregulation of hepatic peroxisome proliferator-activated receptor gamma, a transcription factor for adipogenesis, at the gene level. In conclusion, 10% 2'-FL led to compositional changes in gut microbiota and metabolites associated with improvements in metabolic profiles and gut-brain signaling in HF-fed mice. These findings support the use of 2'-FL for modulating the hyperphagic response to HF diets and improving the microbiota-gut-brain axis

Analysis of trunk and lower extremity electromyographic activity in horizontal whole-body vibration

Whole-Body Vibration (WBV) has been extensively investigated as a widely used training tool. However, previous studies mostly applied the WBV on synchronous or side alternating vibration platform devices. The present study was aimed to investigate the electromyographic activity of trunk and lower-extremity muscles as one stands on a flat floor, and during horizontal whole-body vibration (WBV). This was a comparative cross-sectional study. Sixteen healthy adults participated in the study. The electromyographic activity of the trunk and lower extremity muscles was collected while the participants stood on either a flat floor or a WBV device moving horizontally. Electromyography (EMG) was used to record the activity of trunk and lower extremity muscles (erector spinae, rectus abdominalis, rectus femoris, biceps femoris, tibialis anterior, and gastrocnemius). The rectus femoris, tibialis anterior, and gastrocnemius muscles showed significantly higher muscle activation on the horizontal WBV device than on the flat floor (p<0.05). In particular, the electromyographic activity of Lt. rectus femoris (23.0 vs 14.3), Rt. rectus femoris (32.7 vs 15.1), Lt. tibiailis anterior (19.0 vs 9.8) Rt. tibiailis anterior (17.8 vs 7.9), and of the Lt. gastrocnemius (41.5 vs 15.7), Rt. gastrocnemius (32.7 vs 13.0) increased on the horizontal WBV device than on the flat floor. The muscle activity of the rectus femoris, tibialis anterior, and gastrocnemius muscles proved to be higher when the participants stood on the WBV device vibrating in a horizontal direction than on the flat floor. Further studies need to investigate the clinical applicability of horizontal WBV

PAF-Mediated MAPK Signaling Hyperactivation via LAMTOR3 Induces Pancreatic Tumorigenesis

SummaryDeregulation of mitogen-activated protein kinase (MAPK) signaling leads to development of pancreatic cancer. Although Ras-mutation-driven pancreatic tumorigenesis is well understood, the underlying mechanism of Ras-independent MAPK hyperactivation remains elusive. Here, we have identified a distinct function of PCNA-associated factor (PAF) in modulating MAPK signaling. PAF is overexpressed in pancreatic cancer and required for pancreatic cancer cell proliferation. In mouse models, PAF expression induced pancreatic intraepithelial neoplasia with expression of pancreatic cancer stem cell markers. PAF-induced ductal epithelial cell hyperproliferation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation independently of Ras or Raf mutations. Intriguingly, PAF transcriptionally activated the expression of late endosomal/lysosomal adaptor, MAPK and mTOR activator 3 (LAMTOR3), which hyperphosphorylates MEK and ERK and is necessary for pancreatic cancer cell proliferation. Our results reveal an unsuspected mechanism of mitogenic signaling activation via LAMTOR3 and suggest that PAF-induced MAPK hyperactivation contributes to pancreatic tumorigenesis