Acute Inflammation Is a Predisposing Factor for Weight Gain and Insulin Resistance.

Edson Mendes De Oliveira,Ricardo A Fock,Silvana Sandri,Silene Migliorini,Alexandre F Marchi,Helder T I Nakaya,Jacqueline C Silva,Ana Campa,Thais P Ascar

doi:10.3390/pharmaceutics14030623

Edson Mendes De Oliveira, Ricardo A Fock + Show 7 more

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https://doi.org/10.3390/pharmaceutics14030623

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Abstract

In the course of infection and intense endotoxemia processes, induction of a catabolic state leading to weight loss is observed in mice and humans. However, the late effects of acute inflammation on energy homeostasis, regulation of body weight and glucose metabolism are yet to be elucidated. Here, we addressed whether serial intense endotoxemia, characterized by an acute phase response and weight loss, could be an aggravating or predisposing factor to weight gain and associated metabolic complications. Male Swiss Webster mice were submitted to 8 consecutive doses of lipopolysaccharide (10 mg/kg LPS), followed by 10 weeks on a high-fat diet (HFD). LPS-treated mice did not show changes in weight when fed standard chow. However, when challenged by a high-fat diet, LPS-treated mice showed greater weight gain, with larger fat depot areas, increased serum leptin and insulin levels and impaired insulin sensitivity when compared to mice on HFD only. Acute endotoxemia caused a long-lasting increase in mRNA expression of inflammatory markers such as TLR-4, CD14 and serum amyloid A (SAA) in the adipose tissue, which may represent the key factors connecting inflammation to increased susceptibility to weight gain and impaired glucose homeostasis. In an independent experimental model, and using publicly available microarray data from adipose tissue from mice infected with Gram-negative bacteria, we performed gene set enrichment analysis and confirmed upregulation of a set of genes responsible for cell proliferation and inflammation, including TLR-4 and SAA. Together, we showed that conditions leading to intense and recurring endotoxemia, 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.

Highlights

Introduction published maps and institutional affilMetabolic endotoxemia is low-grade endotoxemia derived from intestinal microbiota and modulated by high-fat feeding
In order to verify the effects of acute endotoxemia on adipose tissue, mice were subjected to eight consecutive LPS challenges (Figure S1a, Supplementary Materials)
During the acute phase response, serum endotoxin (Figure 1a) and serum amyloid A (SAA) (Figure 1b) levels raised over a hundredfold, and mice developed overt signs of endotoxemia, with no animal death

Summary

Introduction

Metabolic endotoxemia is low-grade endotoxemia derived from intestinal microbiota and modulated by high-fat feeding. This condition is known to contribute to weight gain and insulin resistance. Transient and intense endotoxemia is observed along bacterial infections, and it is characterized by a high catabolic process that frequently leads to weight loss [3]. Experimental endotoxemia can be achieved by intravenous or intraperitoneal administration of high doses of lipopolysaccharide (LPS), triggering a pronounced acute inflammatory response similar to that observed during Gram-negative bacteria infections [4]. Acute inflammatory response is regulated by a variety of endogenous factors [5], starting with LPS binding to several host soluble and cell-surface molecules, such as cluster of differentiation

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