Evaluating the evidence for macrophage presence in skeletal muscle and its relation to insulin resistance in obese mice and humans: a systematic review protocol
Bhatt et al. BMC Res Notes
Evaluating the evidence for macrophage presence in skeletal muscle and its relation to insulin resistance in obese mice and humans: a systematic review protocol
Meha Bhatt 2 3
Srikesh Rudrapatna 0 1 2 7
Laura Banfield 6
Rachel Bierbrier 0 2 7
PeiW‑en Wang 0 2 7
KuanW‑en Wang 0 2 7
Lehana Thabane 3 4 5 8
M. Constantine Samaan 0 1 2 3 7
0 Division of Pediatric Endocrinology, McMaster Children's Hospital , Hamilton, ON , Canada
1 Medical Sciences Graduate Program, McMaster University , Hamilton, ON , Canada
2 Department of Pediatrics, McMaster University , Hamilton, ON , Canada
3 Department of Health Research Methods , Evidence, and Impact , McMaster University , Hamilton, ON , Canada
4 Centre for Evalu‐ ation of Medicines , Hamilton, ON , Canada
5 Department of Anesthesia, McMaster University , Hamilton, ON , Canada
6 Health Sciences Library, McMaster University , Hamilton, ON , Canada
7 Division of Pediatric Endo‐ crinology, McMaster Children's Hospital , Hamilton, ON , Canada
8 Biostatistics Unit , St Joseph's Healthcare‐Hamilton, Hamilton, ON , Canada
Objectives: The current global rates of obesity and type 2 diabetes are staggering. In order to implement effective management strategies, it is imperative to understand the mechanisms of obesity‑ induced insulin resistance and diabetes. Macrophage infiltration and inflammation of the adipose tissue in obesity is a well‑ established paradigm, yet the role of macrophages in muscle inflammation, insulin resistance and diabetes is not adequately studied. In this systematic review, we will examine the evidence for the presence of macrophages in skeletal muscle of obese humans and mice, and will assess the association between muscle macrophages and insulin resistance. We will identify published studies that address muscle macrophage content and phenotype, and its association with insulin resistance. We will search MEDLINE/PubMed, EMBASE, and Web of Science for eligible studies. Grey literature will be searched in ProQuest. Quality assessment will be conducted using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias Tool for animal studies. Results: The findings of this systematic review will shed light on immune‑ metabolic crosstalk in obesity, and allow the consideration of targeted therapies to modulate muscle macrophages in the treatment and prevention of diabetes. The review will be published in a peer‑ reviewed journal and presented at conferences.
Obesity; Type 2 diabetes; Insulin resistance; Immunometabolism; Macrophages; Skeletal muscle
Introduction
Type 2 diabetes (T2D) is a major health concern that is
driven by the obesity epidemic [
1
]. As population growth
and longevity rates continue to advance globally,
obesitydriven disorders including cardiovascular disease, stroke
and T2D represent an increasing burden on individuals,
societies, and healthcare systems around the world [
2
].
Identifying the causes of obesity-driven T2D may pave
the way for targeted interventions that treat, and ideally,
prevent these diseases.
The presence of obesity is known to trigger immune
system activity and whole-body inflammation. This
results in a low-grade, chronic inflammatory state
characterized by the production of chemical attractants of
immune cells called ‘chemokines’. Chemokines drive
innate and adaptive immune cells to infiltrate the adipose
tissue [
3
].
The sequence of immune cell involvement in obesity is
complex. Early in the course of obesity, neutrophils enter
the adipose tissue, followed by monocytes. Once
monocytes sense the adipose tissue microenvironment, they
differentiate to classically activated inflammatory (M1)
macrophages that secrete pro-inflammatory cytokines,
leading to adipose tissue inflammation and insulin
resistance [
3
]. On the other hand, another type of macrophage,
with anti-inflammatory actions, known as resident (M2)
macrophage is also present in adipose tissue, and is
responsible for retaining homeostasis by regulating tissue
remodeling and function [
4
].
One theory linking the inflammatory responses in
adipose tissue to muscle inflammation, and subsequent
insulin resistance, suggests that there is a spillage of fatty
acids and cytokines from expanding adipose tissue to the
systemic vasculature. These cytokines and fatty acids are
then able to elicit inflammation at distant organs
including skeletal muscle and the liver [
3
].
Skeletal muscle plays a critical role in glucose
homeostasis, and is prone to insulin resistance due to its
sensitivity to lipotoxicity, glucotoxicity and inflammation. This
might lead to the observed muscle insulin resistance, and
eventual T2D [
5
].
While convincing evidence exists for the presence of
macrophages and inflammation in obese adipose tissue
[
6
], the substantiation of muscle inflammation leading
to insulin resistance is less clear. Some studies have
confirmed the presence of macrophages in muscle of mice
[
6–10
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