Obesity Overview - Signaling Pathway, Diagnostics Marker, Targeted Therapy, and Clinical Trials

1 Main Signaling Pathways in Obesity Pathogenesis

Although the pathogenesis of obesity is not fully understood, it has been recognized as a heterogeneous disease regulated by multiple pathways. A deeper understanding of the signaling pathways involved in the occurrence and development of obesity enables us to combat obesity in a more precise way. These signaling pathways are also important potential targets for new drug treatments to solve obesity.

1.1 MAPK signaling cascade

Mitogen-activated protein kinase (MAPK) is a key mediator of signal transduction in mammalian cells. MAPK signal transduction consists of MAPK kinase (MAPKKK), MAPK kinase (MAPKK), and MAPK and connects extracellular stimulation with intracellular signals. After phosphorylation by MAPK, the downstream transcription factors of this pathway are activated to mediate gene expression and initiate cell responses such as proliferation, inflammation, differentiation, and apoptosis. The cellular molecules on the MAPK signal transduction pathway include extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), and p38 MAPK. These cellular molecules play a key role in appetite, lipogenesis, glucose homeostasis, and thermoregulation. MAPK-mediated appetite regulation and other MAPK functions in the central nervous system (CNS) contribute to the pathogenesis of obesity. ERK signal transduction is essential in the early stages of adipocyte differentiation. P38 MAPK has bifunctional effects on adipocyte differentiation and adipogenesis. There is a complex relationship between obesity and insulin resistance, and the MAPK signal pathway is also closely related to the occurrence of insulin resistance. In addition, brown adipose tissue (BAT) reduces obesity by increasing energy consumption, which is also regulated by MAPK signal transduction.

1.2 PI3K/AKT signaling cascade

The PI3K/AKT signal pathway is a key regulator of cell growth and proliferation. The abnormal activation of this pathway will promote the occurrence of obesity. PI3K and AKT are the two main nodes in this pathway, which are activated by upstream signals such as hormones and growth factors. After activation, PI3K converts PIP2 to PIP3, activates phosphatidylinositol dependent kinase and AKT, and then regulates glycogen synthesis, glucose uptake, and fat production by the GSK3, PKC, and Fox families, respectively. mTOR is one of the key downstream targets of the PI3K/AKT pathway. mTORC1 and mTORC2 play different roles in PI3K/AKT/mTOR signaling pathway, and both of them are closely related to the pathogenesis of obesity. PI3K/AKT pathway can regulate appetite through CNS and peripheral tissue. It is reported that leptin acts on the middle basal part of the hypothalamus, partly through the PI3K-AKT-FoxO1 pathway, to inhibit food intake, and selective inhibition of PI3K will eliminate the effect of leptin. In addition, mTOR also helps to regulate appetite in the central and peripheral systems. The PI3K/AKT pathway also plays a role in thermogenesis.

1.3 JAK/STAT signaling cascade

The JAK/STAT pathway is one of the main intracellular signal transduction pathways and an important downstream medium for various cytokines, hormones, and growth factors. The imbalance of the JAK/STAT signaling pathway leads to obesity either directly or through interaction with other signaling pathways such as MAPK and PI3K. The JAK/STAT signaling pathway is associated with the melanocortin pathway because the energy homeostasis regulated by leptin is mediated by JAK/STAT. The activation of STAT3/STAT5 by the leptin receptor (LEPR) is essential for food intake control. The binding of leptin to LEPR leads to the activation of downstream Rho kinase 1, which phosphorylates and activates JAK2 to maintain energy homeostasis. Fat accumulation in the liver is a feature of obesity. This process is partly regulated by the JAK/STAT signaling pathways of growth factors and cytokines. Studies have consistently shown that hepatocyte-specific STAT3 deficiency can lead to increased insulin resistance and gluconeogenesis gene expression.

1.4 TGF-β signaling cascade

The TGF-β superfamily consists of TGF-β (1-3), activin/inhibin, growth differentiation factor (GDF), myostatin, and BMP, which play multiple roles in appetite regulation, lipid metabolism, and glucose homeostasis. GDF15, a member of the TGF-β superfamily, has been identified as a central appetite regulator and a potential target for obesity treatment. TGF-β signal transduction plays a dual role in adipogenesis/adipocyte differentiation. In adipocytes, TGF-β1 has been shown to be involved in adipose tissue dysfunction associated with obesity. TGF-β signal transduction can also regulate glucose tolerance and energy homeostasis, systematically block TGF-β/Smad3 signal transduction, and increase the expression of PPARγ coactivator 1α (PGC-1α) in adipose tissue to protect mice from obesity, diabetes, and liver steatosis.

1.5 AMPK signaling cascade

There is growing evidence that brain AMPK plays a key role in obesity by regulating food intake, insulin sensitivity, BAT thermogenesis, and WAT browning. Activation of AMPK in the central nervous system can lead to weight gain. It was found that administration of leptin decreased hypothalamic AMPK activity and food intake, while auxin-releasing peptide stimulated hypothalamic AMPK activity and increased food intake.

1.6 Wnt/β-catenin signaling cascade

THE Wnt/β-catenin signal pathway consists of Wnt protein, Frizzled and LRP5/6, Disheveled protein, Axin, GSK3, and β-catenin. The activation/inhibition of the Wnt signaling pathway will lead to different effects on the pathogenesis of obesity. In the classical Wnt pathway, β-catenin is activated by Wnt protein and enters the nucleus to regulate the transcription of target genes. Stimulation of factors such as leptin, OSBPL2, miR-23b, miR-148b, miR-4269, and miR-4429, as well as inhibition of the JAK/STAT3 pathway, CXXC5, and NOTUM, can participate in the pathogenesis of obesity by regulating the Wnt/β-catenin signaling pathway. In addition, Wnt5a can induce obesity-related inflammation in WAT in a JNK-dependent manner, which further leads to insulin resistance in adipose tissue.

2 Diagnosis of Obesity

Obesity is a state of excessive accumulation of fat tissue. BMI is generally used to determine obesity. Currently, the obesity determination standards of the World Health Organization (WHO) and the National Institutes of Health divide BMI into five levels. A BMI of 30 or above is considered obese, and a BMI of 25 or above is considered overweight.

Among those who are judged to be obese (BMI 25 or above), those who meet any of the following conditions:

• Have a health disorder caused by or related to obesity that requires weight loss (to improve or prevent its progression due to weight loss).
• High-risk obesity that is easily complicated by health damage, that is, visceral fat obesity suspected in body measurement screening and confirmed by abdominal CT examination.

3. Targeted Therapy for Obesity

Lifestyle changes are still the basis of weight management, but most patients cannot achieve long-term, meaningful weight loss only through lifestyle changes. Therefore, after the failure of lifestyle change, drug treatment is appropriate. At present, the US Food and Drug Administration (FDA) has approved four short-term (≤ 12 weeks) appetite suppressing obesity drugs (AOM) and five AOM for long-term use. Another drug is used to treat obesity caused by three specific, rare genetic diseases. However, the treatment of obesity itself has been shown to be resistant to treatment to a large extent, and AOM is often ineffective and dubious. Recent research advances are stimulating the pursuit of the next generation of AOM, which seems to be able to safely achieve significant and sustained weight loss.

Table 1. Weight-loss drugs in clinical development after 2015.¹