Campa, A. | Search bioRxiv

bioRxiv2019

Acute inflammation is a predisposing factor for weight gain and insulinresistance

AimIntense endotoxaemia and infection are able to reduce appetite and induce a catabolic state, therefore leading to weight loss. However, it is underexplored its late effects on energy homeostasis, regulation of body weight and glucose metabolism. Here we addressed whether serial intense endotoxaemia, characterized by an acute phase response and weight loss, could be an aggravating or predisposing factor to diet-induced obesity (DIO) and associated metabolic impairments.\n\nMethodsMale Swiss Webster mice were submitted to 8 consecutive doses of lipopolysaccharide (LPS - 10 mg/kg), followed by 10 weeks in high-fat diet (HFD).\n\nResultsAfter the end of the acute endotoxaemia period, mice under chow diet recovered their weight rapidly, within one-week recovery period, which remained similar to its control counterparts. However, acute endotoxaemia caused a long-lasting adipose tissue expression of the inflammatory markers TLR-4, CD14 and serum amyloid A (SAA) and, when challenged by a HFD, LPS-treated mice gained more weight, showed increased fat depots, leptin and insulin levels, and also impaired insulin sensitivity.\n\nConclusionsLPS-treated mice showed a higher susceptibility to the harmful effects of a subsequent HFD. Conditions leading to intense and recurrent endotoxaemia, such as common childhood bacterial infections, may resound for a long time and aggravate the effects of a western diet. If confirmed in humans, infections should be considered an additional factor contributing to obesity and type 2 diabetes epidemics and additionally impose more rigorous dietary recommendations for patients in post-infection recovery.\n\nBullet pointsO_LIIntense endotoxemia causes a long-lasting increase in the expression of inflammatory markers in adipose tissue.\nC_LIO_LIIntense endotoxemia is a predisposing factor to diet-induced obesity and insulin resistance.\nC_LIO_LIInfections may contribute to weight gain when associated to a western diet.\nC_LI

cell biology↗

bioRxiv2019

1-Methyl-tryptophan enantiomers differently affect the cross- talking between mononuclear and tumor cells and interferon-γ production.

The inhibition of the enzyme indoleamine-2,3-dioxygenase (IDO), that catalyzes the oxidation of the amino acid tryptophan to kynurenine (KYN), is considered a good target for immunoadjuvants in antineoplastic therapy. 1-Methyl-tryptophan (1-MT) is the most studied molecule for this purpose. Although L-1-MT is better than D-1-MT in inhibiting IDO, for an unknown reason the D-enantiomer has higher clinical efficacy. Here we took advantage of co-cultures of tumor cells (SK-Mel 19 melanoma line; 1x105 cells/well) with peripheral blood mononuclear cells (PBMC; 5x106 cells/well) to verify the effect of 1-MT enantiomers on cytokine production and tumoricidal activity. At a concentration that did not affect KYN production, 1-MT (50 {micro}M) affected the production of TNF-, IL-10, and IFN-{gamma} measured in co-cultures supernatants. Stereospecificity was only observed for IFN-{gamma} production. D-1-MT inhibited more than 30% of IFN-{gamma} production, while L-1-MT had no effect. Stereospecific effect was also seen in PBMC tumoricidal activity, estimated by tumor cell viability (Trypan assay). The racemic mixture DL- and D-1-MT almost doubled the tumoricidal activity of PBMCs, while L-1-MT had no effect. These are previous unknown off-target effects of D-1-MT. Our data suggest the modulation of IFN-{gamma} and the activation of tumor recognition and killing processes by immune cells as important features for the in vivo effects of the D-1-MT. These findings should be considered in future studies of immunoadjuvants for cancer treatment.

pharmacology and toxicology↗