**5. Could targeting macrophages provide a therapeutic strategy in metabolic disorders?**

As described above, as macrophages play a significant role in obesity and other metabolic disorders they are an attractive therapeutic target. The therapeutic strategies that target macrophages look to re-educate polarized macrophages, depletion of polarized macrophages or silencing macrophages. Additionally, the link between macrophage polarization and cellular metabolism suggests a potential therapeutic strategy by modulating the macrophage metabolic state. There are several therapeutic strategies commonly used to target macrophages such as depletion, proliferation, inflammation and gene silencing.

### **5.1 Macrophage depletion**

It was shown that macrophages could be depleted *in vivo* by inducing apoptosis following accumulation of toxic particles [93]. Interesting, it was shown that by depletion of pro-inflammatory macrophages resulted in normalizing insulin sensitivity in IR obese mice [94]. Furthermore, in obese mice, the depletion of visceral adipose tissue macrophages (VATMs) by Intraperitoneal injection of clodronate liposomes, results in improved systemic insulin sensitivity, glucose homeostasis and further blocked high-fat diet-induced weight gain [95, 96]. Consequently, depletion of VATMs also resulted in prevention of CLS in WAT and a low level of blood TNF-α [96]. However, liposomes treatment as a therapy is prone to degradation and significant risks of potential off-target effects. An alternative approach is altering macrophage proliferation, such as using a nanoparticle-based delivery of simvastatin, which may provide therapeutic benefit for atherosclerosis [97]. However, as previously mentioned, in obesity, macrophages are recruited from circulating monocytes, so reducing proliferation may not provide therapeutic benefit for IR [98].

#### **5.2 Biological therapeutics**

There are several orally active synthetic ligands for PPARɣ which are used to treat IR in patients with T2D. It has been shown *in vivo* that pioglitazone, belonging to the chemical class thiazolidinediones, reduces LPS induced TLR2 and TLR4 expression on peritoneal macrophages. Whilst *in vitro*, pioglitazone reduces the synthesis and gene expression of TLR2, TLR4, IL-1β, TNF-α, IL-6 and MCP-1 in human blood monocytes [99]. However, the use of thiazolidinediones like pioglitazone in clinical studies to treat T2D has resulted in increased cardiovascular events and death [100].

Clinical studies have shown that anti-inflammatories are efficacious in patients with systemic IR. Members of the interferon family have been used to suppress the release of pro-inflammatory cytokines, however, the use of type 1 interferons, as well as other anti-inflammatory strategies, is associated with cell toxicity in longterm use. Recently studies using interferon tau (IFNT), an alternative member of the type 1 interferon family, in mice with diet-induced obesity show enhanced insulin sensitivity when compared to untreated mice. There was also a significant decrease in secretion of pro-inflammatory cytokines and increased M2 macrophages in AT, suggesting IFNT as a novel bio-therapeutic agent for treating obesityassociated disorders [101].

Interestingly, yeast-derived β-glucans (Y-BGs) have been shown to be beneficial in models for obesity. In obese humans, Y-GBs administered orally increased AT

expression of anti-inflammatory cytokine IL-10 and serum IL-10 [102]. In addition, macrophages uptake of Y-GBs increased reactive oxygen species (ROS) formation, phagosomal maturation and induction of autophagy [103].

#### **5.3 RNA interference**

Another attractive therapeutic approach in targeting macrophage polarisation would be to use RNA interference (RNAi), which reduces gene expression. This approach could target the inflammatory mediators such as TNF-α, IL-6 and IL-1β [98]. Indeed, it was shown that intraperitoneal (i.p.) administration of small interfering RNA (siRNA) selectively silenced genes such as TNF-α in epididymal ATM of obese mice and improved glucose tolerance [7]. Additionally, it was shown that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptorbinding peptide delivers siRNA into ATM and peritoneal macrophages in HFD mice. This resulted in inhibition of ATM infiltration and reduced pro-inflammatory cytokines, thus improving glucose tolerance and insulin sensitivity [104].

#### **5.4 Metabolic reprogramming**

As stated previously, macrophage phenotypes have distinct metabolism pathways. Therefore, altering the metabolic state of macrophages provides a potential therapeutic approach to metabolic disorders. Indeed, the strong link between macrophage polarization and cellular metabolism makes altering the metabolic state of the cells an attractive therapeutic prospect. To prove this principle, inducing oxidative metabolism in M1 macrophages has been shown to shift the phenotype to an M2 profile [105], while blocking oxidative metabolism in macrophages inhibits the M2 phenotype and drives the M1 macrophage phenotype. Furthermore, it was shown that by driving macrophage metabolism with glucose, insulin and fatty acids resulted in an increased pro-inflammatory ATM phenotype in obese mice [32].

Modulation of the metabolic pathways in macrophages has been studied extensively in recent years to assess the extent to which inflammatory status can be influenced by the metabolic profile of the cells. Glucose transporter (GLUT)-1 is upregulated in macrophages localised to the CLS in inflamed obese AT. *In vitro* studies show that overexpression of GLUT1 increases glucose uptake in the cells and induces release of pro-inflammatory cytokines, linking the metabolic phenotype with the inflammatory function of the cells [106]. Furthermore, knockout of fatty acid transporter protein (FATP)-1 expression, which is elevated in M2 macrophages, is associated with priming of macrophages towards an M1 phenotype, upregulating expression of NOS1 [107]. Further pathways of current interest to therapeutically target include Notch, carbohydrate kinase-like protein (CARKL), mammalian target of rapamycin (mTOR), IL-4 and IL-10, all of which show intricate links between the metabolic and inflammatory pathways in macrophages [108–112].

#### **6. Conclusions**

Obesity has long been considered a low-grade systemic inflammatory condition, which appears to be mediated largely through the prominent populations of ATM. Alterations in environmental cues, including changes in metabolites, the microbiota and inflammatory stimuli act to influence the ATM, coordinating the recruitment of pro-inflammatory monocytes and altering the metabolic state of ATM. While in lean individuals the resident ATM function to clear dead adipocytes and sequester excess lipids from the AT to maintain homeostasis within the AT,

*The Pivotal Role of Macrophages in Metabolic Distress DOI: http://dx.doi.org/10.5772/intechopen.86474*

the recruited inflammatory ATM release pro-inflammatory cytokines to induce inflammation within the AT and are involved in the pathogenic remodelling of the AT. This state of inflammation within the ATM is largely associated with IR and metabolic dysfunction through interference with insulin signalling pathways. Macrophages are heterogenous and extremely plastic and as such it has historically been difficult to define subsets. With the use of transcriptional and metabolic profiling it is now becoming possible to appraise the full role of ATM in obesity. This knowledge will aid the search for novel therapeutics targeting the metabolic capacity and inflammatory potential of ATM, restoring the homeostatic functions of resident lean ATM, to modulate obesity.
