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Obese Signaling Pathway

Obesity means a person who's very overweight, at least 20% higher than it should be. It's a common problem in the US and worldwide. According to National Health and Nutrition Examination Survey (NHANES) data, it's estimated to affect around 30% adults and around 20% children aged 10 to 11. For children, rates of obesity have risen even faster. Obesity is the second cause of death in the world and has reached epidemic proportions in recent years.

An Overview of Obesity

Obesity and overweight involve an abnormal and excessive fat accumulation that negatively affects the health status. According to the World Health Organization (WHO), if body mass index (BMI) is equal or greater than 25 kg/m2, it is considered overweight, whereas the BMI higher than 30 kg/ m2 defines obesity (Figure 1). It stems from a positive mismatch between energy intake and energy expenditure. Western societies are “obesigenic” environments where people have become sedentary while food portions have grown “super-sized” and highly processed convenience foods and soft drinks provide a glut of calories throughout the day.

The definition of obesity

Figure 1. The definition of obesity.

Actually, obesity is a consequence of complex interactions among genetic, environmental, socio-economic and dietary factors. The rapidity at which obesity is increasing in westernized or socio-economically developed countries is not fully explained by traditional theories of weight gain. Lifestyle factors particularly in early life, such as exposure to antibiotics, and other early life environmental modifiers which may be linked with epigenetic changes, are coming under scrutiny as risk factors for obesity later in life. Characteristics of obesity include low-grade inflammation, altered microbiota, and increased tone of the endocannabinoid system (Figure 2).

The characteristics of obesitys

Figure 2. The characteristics of obesity. (Moran, C.P; et al. 2014)

The Process of Obese Signaling Pathways

Obesity individuals secrete less adiponectin than lean individuals. The decreased production of adiponectin, in combination with the inability of adipose tissue to store the surplus free fatty acids (FFAs), can be considered to reflect adipose tissue dysfunction. Under normal conditions, adiponectin increases insulin sensitivity directly, by stimulating tyrosine phosphorylation of the insulin receptor. Adiponectin, binding to adipo-receptor R1/R2, can activate 5′-AMP-activated protein kinase (AMPK), leading to increased fatty acid oxidation and decreased influx of FFAs into the liver. Independent of AMPK activation, adiponectin decreases the production of reactive oxygen species (ROS), which may result in decreased activation of mitogen-activated-protein-kinase (MAPK) and thereby inhibition of cell proliferation.

FFAs signaling pathway

FFAs are increased in obesity and are implicated as proximate causes of insulin resistance and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines and other factors that affect insulin signaling and result in the development of insulin resistance which is frequently seen in obesity. Obesity induces lipolysis and release of pro-inflammatory FFAs and factors, such as tumor necrosis factor alpha (TNF-α). TNF-α initiates signaling through tumor necrosis factor receptor 1 (TNFR1) with the consequent regulation of gene expression, recruiting TNFR1-associated death domain (TRADD), TNF receptor-associated factor-2 (TRAF2), and receptor-interacting protein (RIP). They then induce TGFβ-activated kinase 1 (TAK1) and TAK1-TAB complex which activates NF-κB essential modulator (NEMO), IKKα, and IKKβ, inhibiting insulin receptor substrate (IRS). The activation of the IκB kinase leads to phosphorylation of IκB and release of NF-κB, which then translocates to the nucleus and binds to the promoters of pro-inflammatory genes and initiates transcription.

Insulin signaling pathway

Insulin binding to insulin receptor (IR), leads to the activation of receptor tyrosine kinase and receptor phosphorylation, which enables the binding of docking proteins such as insulin receptor substrates (IRS). It then stimulates cell proliferation through several downstream signaling networks, including the phosphatidylinositol 3-kinase (PI3K) -AKT system, mammalian target of rapamycin (mTOR), and the MAPK systems.

SFAs signaling pathway

Saturated fatty acids (SFAs) are the major type of fats including lauric, myristic, palmitic and stearic acids. They can bind to Fetuin-A, an endogenous ligand of toll-like receptor 2 (TLR2) or TLR4, and initiate transcription of interferon regulatory factor 3 (IRF3) by activating the myeloid differentiation primary response protein 88 (MyD88)-TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathway. TNF receptor-associated factor-3 (TRAF3) is a ubiquitin ligase recruited to both MYD88 and TRIF-assembled signaling complexes. The IKK-related kinases (TBK1) and IKKε activate IRF3, and activated IRF3 then translocates to the nucleus and binds to target DNA sequences.

The Therapy for Obesity

Obesity is a chronic disease and is associated with numerous comorbidities, including type 2 diabetes mellitus (T2DM), cardiovascular disease, hypertension, and dyslipidemia. Moreover, obesity is a risk factor for major causes of morbidity and mortality and increasing evidence shows that a binge eating disorder (BED) affects a subset of obese patients. The prevalence of obesity and related disorders have skyrocketed worldwide despite efforts to therapeutically target homeostatic mechanisms that regulate appetite, energy expenditure, and weight gain. The failure of these efforts points to the existence of additional, non-homeostatic mechanisms that mediate feeding behavior. Indeed, redundancy in these pathways makes obesity therapy difficult as it is further evidenced by the failure of newer drugs targeting distinct aspects of these systems. Thus, the epidemic of obesity begs for novel concepts and therapeutic targets that ideally treat ‘food-use’ disorders and related comorbidities such as drug addiction and neuropsychiatric disorders.

References:

1. Ray, I; et al. Obesity: an immunometabolic perspective. Front Endocrinol (Lausanne).2016, 7:157.
2. Moran, C.P; et al. Gut microbiota and obesity: Role in aetiology and potential therapeutic target. Best Practice & Research Clinical Gastroenterology. 2014, 28 (4): 585-597.

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