The role of Wnt pathway in obesity induced inflammation and diabetes: a review

Abstract

Diabetes has become a major killer worldwide and at present, millions are affected by it. Being a chronic disease it increases the risk of other diseases ranging from pulmonary disorders to soft tissue infections. The loss of insulin-producing capacity of the pancreatic β-cells is the main reason for the development of the disease. Obesity is a major complication that can give rise to several other diseases such as cancer, diabetes, etc. Visceral adiposity is one of the major factors that play a role in the development of insulin resistance. Obesity causes a chronic low-grade inflammation in the tissues that further increases the chances of developing diabetes. Several pathways have been associated with the development of diabetes due to inflammation caused by obesity. The Wnt pathway is one such candidate pathway that is found to have a controlling effect on the development of insulin resistance. Moreover, the pathway has also been linked to obesity and inflammation. This review aims to find a connection between obesity, inflammation, and diabetes by taking the wnt pathway as the connecting link.

Introduction

Diabetes mellitus is a type of metabolic disorder in which there is a chronic high level of blood glucose resulting from an insufficient amount of insulin being produced by the body or due to the inability of insulin to act on cells [1]. It is a major killer worldwide and it has seen an unprecedented rise in recent years, thus posing as a serious threat to mankind. According to a recent estimation, about 387 million people worldwide are affected by the disease, with a prevalence rate of 8.3% and 46.3% still remains undiagnosed [2]. Being a chronic condition, diabetes tends to increase the overall risk of several other diseases caused by macro-vascular and microvascular damage and has negative impacts on several organs, such as the brain, kidney, heart, and eyes [3]. Moreover, several studies have reported an increased risk of lower respiratory tract infections such as pulmonary tuberculosis [4–6] and pneumonia [7–10], urinary tract infections [11, 12], and skin and soft tissue infections [13–15] in people with diabetes. There are two major classes of diabetes—type 1 and type 2. Type 1 diabetes (T1D) is a type of autoimmune disorder in which the patient’s T cells attack and destroy the pancreas. This causes the pancreas to lose its ability to produce insulin completely and therefore it is unable to act upon the cells. T1D is usually seen to be present at a very young age and is often called childhood-onset diabetes [16, 17]. Whereas, type 2 diabetes (T2D) is caused by a combination of a variety of genetic, environmental, and lifestyle factors. It is commonly considered to be a lifestyle-associated chronic disease [18]. β-cell dysfunction in the pancreas causes the development of insulin resistance. This leads to the occurrence of T2D as the pancreas is unable to cope with the increased demands for insulin [19]. It is estimated that there are more than 285 million people with T2D in the world, making up about 90% of all diabetes cases [20–22]. High BMI (Body Mass Index) associated with obesity mostly contributed to diabetes, with a general increase in disability-adjusted life-years (DALYs) rate (80.4%) and mortality rate (73.5%) since 1990 [23].

Obesity in recent years has become a major complication that is associated with many diseases including cancer [24], diabetes [25], etc. It has been found that visceral adiposity plays a major role in the development of insulin resistance, hyperlipidemia, etc. in patients [26]. Obesity results in the development of a chronic low-grade inflammation along with immune system activation that plays a vital role in the pathogenesis of obesity-related metabolic disorders [27–30]. Various pieces of evidence have suggested that chronic inflammation also increases the risk of obesity and diabetes [27]. Moreover, various pathways have been found to have a controlling effect on the development of insulin resistance and diabetes [31, 32]. The Jak-Stat pathway is involved in preventing pancreatic beta-cell damage in high-fat diet-induced diabetes [33]. Similarly, the Wnt signaling pathway is involved in inflammatory as well as anti-inflammatory activity [34] and the promotion of beta-cell protection in obese and diabetic individuals [35]. In the present review, the major emphasis will be on studying the role of obesity and inflammation in diabetes with special reference to the Wnt signaling pathway (Fig. 1).

Fig. 1.

The Wnt/β-catenin pathway. a Fate of β-catenin in the absence of Wnt ligand. b Activation of the pathway by Wnt and the subsequent action of β-catenin

Obesity and insulin resistance

Obesity is a very serious disease that causes many major complications. It leads to the impairment of many vital functions of the human body [24]. Diseases such as non-insulin-dependent diabetes mellitus (NIDDM), cardiovascular disease, obstructive pulmonary disease, arthritis, cancer [24], and diabetes [25, 36] make up the major complications associated with obesity. The current increase in the prevalence of obesity has been associated with an increase in the prevalence of type 2 diabetes [37, 38]. Obesity increases the chances of developing insulin resistance and glucose intolerance [39]. Thus, it further complicates the management and treatment process of type 2 diabetes [40]. Obesity, especially excess visceral adiposity, is associated with insulin resistance, hyperglycemia, dyslipidemia, and hypertension. Together they are termed as the “metabolic syndrome” [26]. Several studies have found that there appears to be a direct correlation between diabetes and insulin resistance. In the Nurses’ Health Study conducted for 16 years, it was found that a BMI of 30.0 to 34.9 kg/m2 increased the risk of diabetes by 20.1-fold. Whereas, a BMI of 35 kg/m2 or greater increased the risk by 38-fold [41]. Obese patients suffering from type 2 diabetes show that a reduction in abdominal fat and weight loss leads to improvements in glycemic control, insulin sensitivity, and lipid profile [42, 43].

Role of inflammation during obesity and T2D

Inflammation is a type of protective response that enables the host organism to cope with various stresses from external factors. It can be classified as either acute or chronic [44]. Acute inflammation leads to the development of prominent local and systemic symptoms, which is accompanied by infiltration of the affected area by immune cells, mainly neutrophils. On the other hand, chronic inflammation causes less prominent local and systemic symptoms but shows enhanced tissue injury and fibrosis, accompanied by the infiltration of the affected area mainly with monocytes/macrophages and lymphocytes [44]. A chronic low-grade inflammation along with the activation of the immune system is observed in abdominal obesity. It may play a major role in the pathogenesis of different obesity-related metabolic disorders [27–30]. Various experiments have shown that adipose tissue, liver, muscle, and pancreas are the major sites of inflammation during obesity and T2D. Macrophage and inflammatory cell infiltration are commonly seen in the tissues of animal models of obesity and diabetes [45]. It has also been observed in obese human individuals with metabolic syndrome or T2D [46–49].

Various evidence suggests that due to chronic activation of proinflammatory pathways in target cells of insulin action there is an increased risk of obesity, insulin resistance, and related disorders including type 2 diabetes [27]. It has been found that free fatty acids and several other metabolites are produced by the fat tissues in our bodies. Metabolites such as acyl-CoAs, ceramide, and diacylglycerol act as signaling molecules that activate the inflammatory cascade associated with insulin resistance [50]. Macrophages are of two different types, the first is the classically activated macrophage also known as M1, and secondly, the alternately activated macrophages which are known as M2 [29]. During obesity, it has been seen that there is a phenotypic switch from M2 to the M1 phenotype [51, 52]. Generally, M2 macrophages produce anti-inflammatory cytokines such as Interleukin 10 (IL-10) and protect against the development of obesity-related insulin resistance. But, the M1 macrophages produce various pro-inflammatory cytokines such as Interleukin 6 (IL-6), Tumour Necrosis Factor-alpha (TNF-α), etc. which activate direct and paracrine signals leading to the impairment of insulin signaling [29]. Pro-inflammatory markers such as plasminogen activator inhibitor 1 (PAI-1), C-reactive protein (CRP), serum amyloid A (SAA), TNF-α, interleukin (IL-1β, IL-6), leptin, macrophage chemo-attractant protein-1 (MCP-1), and chemokines are at elevated levels in the obese and T2D patients and are positively related with insulin resistance [53–64]. Studies have shown that these markers along with many other indirect markers can be used to detect or predict T2D [65–67]. These pro-inflammatory cytokines and chemokines lead to the activation of various stress pathways inside the cells, such as the c-Jun N-terminal kinase (JNK) and NF-κB pathway [59], IL-6 signaling [68], Phosphoinositide 3- kinase (PI3-K) pathway [69], Wnt signaling pathway [70], etc.

The possibility of the presence of pathways linking inflammation to diabetes mellitus has sparked a new research interest in targeting inflammation to improve the prevention and control of diabetes and other related complications [71] (Fig. 2).

Fig. 2.

The action of Wnt/β-catenin pathway in the Adipocytes in presence of different Wnt ligands. a Ligands like Wnt3a and Wnt10b inhibits Adipogenesis by activating the β-catenin dependent Wnt pathway. This prevents the onset of Obesity. b Ligands Wnt5a and Wnt5b inhibits the β-catenin dependent Wnt pathway but activates β-catenin independent Wnt pathway. They also causes overexpression of adipogenic markers such as PPARγ (Peroxisome proliferator-activated receptor gamma) and αP2 (Adipocyte protein 2). All this contributes to the activation of Adipogenesis leading to Obesity

WNT pathway

The Wnt signaling pathway is an integral part of many fundamental cellular functions such as proliferation and maintenance of stem cells (e.g., the intestinal stem cell compartment), development, organogenesis, etc. [72, 73]. The signaling pathway is induced by the binding of Wnt ligands to the frizzled and LRP5/6 (Lipoprotein receptor-related protein) intermembrane cell surface receptors. Due to the association of the receptor and ligand, the Wnt signal is transmitted via Dishevelled (Dvl) to the degradation complex of APC (Adenomatous Polyposis Coli), Axin, glycogen synthase kinase-3 beta (GSK-3b), beta-catenin (β-catenin), and other proteins. This stops the degradation of β-catenin resulting in the accumulation of active, dephosphorylated beta-catenin [73, 74]. Dephosphorylated β-catenin then interacts with Tcf/Lef (T cell factor/Lymphoid enhancer factor) DNA binding proteins [73]. These β-catenin-Tcf (BCT) transcriptional complexes can drive the transcription from Tcf site-containing promoter constructs [73], and, upon binding to the Tcf sites in DNA, they activate the transcription of Wnt target genes. In the absence of the Wnt signal, this degradation complex phosphorylates β-catenin and targets it for proteasomal degradation [73, 75, 76], which prevents the transcription of the Wnt target genes (Fig. 3).

Fig. 3.

Effects of different levels of Wnt signaling on the Pancreatic β-cells. Moderate level of Wnt signaling promotes the proliferation of β-cells and stimulates proper function. Thus, preventing onset of Obesity and Diabetes. Whereas, Low level of Wnt signaling produces Diabetic β-cell phenotypes and promotes Obesity and Diabetes

WNT pathway and its role in obesity

The Wnt pathway and its effector molecules have important metabolic and developmental roles in the adipose tissues of our body [77, 78]. Along with that, it has been found that several Wnt components, multiple Wnt ligands, and receptors are found on the fully mature adipocytes. [79, 80]. The Wnt pathway has been found to play a very important role in the development of both White Adipose Tissues (WATs) and Brown Adipose Tissues (BATs) [81–87]. Wnt/β-catenin pathway upon activation leads to the inhibition of adipogenesis in these tissues. Members of the Wnt family such as Wnt3a and Wnt10b are involved in the activation of the pathway causing inhibition of adipogenesis [77, 78, 88, 89]. Whereas, several Wnt ligands, such as Wnt4, Wnt5a, and Wnt5b promote the stimulation of adipogenesis by preventing the activation of the Wnt/β-catenin pathway [90, 91]. It was found that Wnt5b promoted adipogenesis in the preadipocytes [92, 93]. TCF7L2 (Transcription factor 7-like 2) gene is greatly expressed in the adipose tissue and is involved in the regulation of adipogenesis through Wnt/β-catenin signaling [77, 94–96]. LRP5/6 is one of the coreceptors of the Wnt pathway and mutations in it such as the LGR4 (Leucine-rich repeat-containing G-protein coupled receptor 4) gave one of the best evidence of the involvement of the Wnt pathway in Obesity [97, 98]. It was found that increased LGR4 activity promoted human obesity [99–103]. Zeve [104] demonstrated that alteration in the Wnt signaling led to the disrupted development of adipocytes. The mature adipocytes could regulate the process of adipogenesis by secreting various factors [105]. Based on that and other evidence it was hypothesized by Chen and Wang [106] that Wnt signaling regulated these secretions from the adipocytes. The Wnt pathway also causes activation of these adipocytes and leads to their over-proliferation which is crucial for obesity development [106, 107].

WNT pathway and obesity-related inflammation

Wnt signaling is a regulator of adipogenesis as it prevents the preadipocytes from differentiating [77]. In recent years, it has been found that wnt signaling plays a part in both inflammatory and anti-inflammatory pathways [108]. The inflammatory roles of wnt pathway proteins vary from tissue to tissue. Various proinflammatory cytokines such as TNF-α and IL-6 are produced by macrophages and adipocytes that promote inflammation and favors obesity and diabetes [109]. Canonical wnt signaling upon activation prevents the accumulation of these inflammatory cytokines and also regulates the preadipocytes in an undifferentiated form [77, 110]. However, non-canonical wnt ligands such as Wnt5a are expressed in adipocytes at high levels when the diet consists of fatty substances. It contributes to obesity-associated inflammation [34, 111–113]. LRP-1 (lipoprotein receptor-related protein 1) is a low-density lipoprotein receptor of the LDLR (Low-density lipoprotein receptor) family. It is expressed in the adipocytes and has been related to multiple pathways [114, 115]. sFRP-5 (Secreted Frizzled Related Protein 5) is an anti-inflammatory molecule that prevents metabolic dysfunction during obesity by binding to the Wnt5a ligand and preventing it from activating the Wnt signaling pathway [77]. LRP-1 Binds to sFRP-5 directly and causes its cellular degradation. Upon removal of the inhibitor, the Wnt ligands can activate the Wnt pathway and cause adipose tissue inflammation, obesity, and glucose homeostasis [112, 113, 116].

Role of wnt pathway in diabetes

The possibility of a link between the wnt pathway and diabetes was first established when deCODE Genetics identified a link between the TCF7L2 gene and an important component of the Wnt pathway [95]. TCF7L2 is a major diabetes susceptibility gene and has one of the biggest effects in the development of type 2 diabetes [95, 117–122]. It has also been found that the Wnt pathway plays a role in GLP-1 (Glucagon-like peptide 1) production [123, 124], pancreatic β-cell proliferation [35, 125, 126], cholesterol metabolism, and glucose-induced insulin secretion [127]. Different levels of wnt activity in a tissue can result in varying physiological outputs. Moderate levels of wnt activity are necessary for pancreatic β-cell proliferation [128–130]. In absence of wnt signaling the Tcf factors cannot form the β-catenin-Tcf complex and act as repressors of the Wnt target genes [131, 132]. Thus, alteration of Tcf expression can influence the Wnt pathway in the pancreatic β cells leading to change in the cell physiology and development of diabetic phenotype [133, 134]. This was attributed to the fact that the TCF7L2 gene was located in the same region of chromosome 10 that has been associated with diabetes [135, 136]. GLP-1 is a peptide hormone that promotes glucose-dependent insulin secretion and other anti-diabetogenic activities through the wnt pathway [35, 123, 124, 137]. Overexpression of the TCF7L2 gene suppressed the expression of GLP-1 and resulted in reduced GLP-1 induced insulin secretion [133, 138]. Also, low-level expression of the Tcf gene reduced insulin gene expression as well as secretion of insulin by the pancreatic β-cells [139]. Thus, both high and low-level expression of the Tcf gene led to inhibition of the wnt pathway resulting in the development of Diabetic β-cells [128]. However, in the presence of β-catenin, the Tcf factors resulted in activation of wnt signaling and promoting pancreatic cell viability [126, 128, 138]. Thus, the above condition arose only when the levels of β-catenin decreased [129].

In addition to polymorphisms in Wnt5B, a wnt-related gene has been associated with an increased risk of type 2 diabetes [92, 140]. Similarly, the LRP5 gene has been linked to type 1 diabetes and obesity [97, 141–143]. Rulifson et al. [125], showed that ligands such as Wnt3a stimulated the proliferation of pancreatic β cells in mice possibly through the cell cycle regulators such as cyclins and cyclin-dependent kinases (cdks). Moreover, Wnt molecules derived from adipocytes have been reported to induce pancreatic β cell proliferation and insulin secretion [79]. The co-receptors LRP5/6 play important roles in normal lipid and glucose metabolism [144, 145]. It has also been found that Wnt ligands such as Wnt3a and Wnt5a require a functioning LRP5 to activate the pathway and thus regulate insulin secretion [146]. Wnt5a ligand generally contributes to an increased risk of obesity-associated inflammation [111–113]. Frizzled related protein such as sFRP-5 can modulate the metabolic dysfunction in obese patients by binding to Wnt5a and thus preventing it from activating the Wnt pathway [77]. This promotes anti-inflammatory activity and glucose tolerance in diabetic patients [34, 116]. During aging, there is an increase in ROS (Reactive Oxygen Species) production and activation of the JNK pathway leading to increased nuclear FOXOs (Forkhead Box protein class O)[147]. FOXO competes with TCF proteins for the available β-catenin and reduces the activity of Wnt signaling. This negatively affects lipid and glucose metabolism, pancreatic β-cell proliferation and function, and production of GLP-1 which helps in the pathogenesis of type 2 diabetes [148]. The presence of more than one factor relating the Wnt pathway to diabetes proves the presence of a relationship between the two (Table 1).

Table 1.

The various factors that act as triggers of inflammation in obesity and diabetes

Factors	Effects
Obesity	Increase of mass causes adipose tissues to be hypoxic due decrease in vasculature. This hypoxia triggers inflammation in the tissues [149–152]
Diet	High-fat diet causes development of Gram -ve bacteria in the gut leading to increased lipopolysaccharide production. This triggers inflammation [153, 154]
Oral health	Infections such as periodontitis causes low grade systemic inflammation that may affect the health and cause diabetes [155, 156]
Gut Microbiota	LPS produced by the Gram − ve bacteria produces low grade inflammation that leads to obesity and diabetes [157]
Air pollution	Long term exposure to polluted air leads to increase chances of diabetes occurrence and diabetes related mortality due to inflammation caused by oxidative stress [158, 159]
Vitamin D Defiency	Vitamin D has anti-inflammatory role and its deficiency plays a major role in he development of insulin resistance [160, 161]
Genetics	Single nucleotide polymorphisms are seen in the regulatory regions of many inflammatory and pro-inflammatory genes and these SNPs affect the intensity of inflammation. It is seen in several cases of diabetes and obesity [162–164]

β-cell protection is a major aim in the treatment of type 2 diabetes. Various compounds are being utilized in recent years for the treatment of diabetes that act by stimulating the Wnt activity in the pancreatic β-cells in vitro. This results in the activation of Wnt-mediated pancreatic β-cell proliferation [35] and the promotion of anti-inflammatory activity and glucose tolerance [116] (Table 2)

Table 2.

Different inflammatory markers of diabetes

Markers	Source	Inflammatory role
White blood cell counts	Blood	Elevated levels of white blood cells is seen in type 2 diabetes Macrophages are the main cells associated with inflammation during diabetes
Adipokines	Adipose tissues	Leptin is a positive regulator of glucose homeostasis and leptin resistance is usually seen in obesity and diabetes Resistin induces insulin resistance and stimulates TNF and IL-6 production Adiponectin is anti-inflammatory, suppresses activation of macrophages and prevents development of insulin resistance. Impairs cytokine production
Chemotactic proteins Chemokines Cytokines	Adipocytes and other cells of adipose tissue Adipocytes and immune cells	Chemokines such as Chemokine (C–C motif) ligand 2 (CCL2), CCL5 and IL-8 are related to diabetes. They attract immune cells to the adipose tissues and promote inflammatory response TNF-α has proinflammatory properties. It causes release of fatty acids fromadipocytes causing destruction of insulin signaling which reduces insulin secretion IL-6 is proinflammatory and is released by the immune cells. It is found in high concentration in blood plasma during diabetes IL-10 is anti-inflammatory and it has insulin sensitizing effects. It inhibits cytokines such as TNF-α and IL-6. Decrease in IL-10 is associated with diabetes
Acute Phase Proteins (C-Reactive Protein)	Liver	Secretion of CRP is induced by IL-6 and othe proinflammatory cytokines. It may lead to insulin resistance by altering of the insulin pathways

Conclusion

The Wnt pathway is involved in many fundamental cellular processes across a variety of tissues in our body including the adipose tissues. The pathway, its various components, and effector molecules have important metabolic and developmental roles in adipose tissues. It acts as a regulator of adipogenesis and is involved in both inflammatory as well as anti-inflammatory pathways. Several wnt ligands stimulate adipogenesis by activating the Wnt/β-catenin pathway leading to the overproliferation of the adipocytes. The same ligands also contribute to obesity-associated inflammation in the adipose tissues largely via this pathway. This causes the development of insulin resistance seen during diabetes. Moreover, the pathway is involved in pancreatic β-cell proliferation, cholesterol metabolism, and insulin production. In absence of wnt signaling the cell physiology of the pancreatic β-cells changes to give rise to diabetic phenotypes. Thus, the same pathway plays different roles in different tissues but ultimately contributes to the pathogenicity of diabetes. In the adipocytes, the activation of the pathway leads to overproliferation and obesity which ultimately contributes to diabetes. whereas, in the pancreatic β-cells the inhibition of the pathway causes the development of diabetic phenotype with reduced insulin production. The presence of a correlation between all these factors in contributing to the development of diabetes can be seen in this review. In recent years, the study of the wnt pathway has seen an increase with the hope of finding a cure for diabetes. The targeting of some important wnt components might provide an effective treatment for diabetes in the future.

Author Contributions

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Funding

Council of Scientific & Industrial Research, Human Resource Development Group (CSIR-HRDG), New Delhi (India).

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