Mechanistic Links Between Obesity and Airway Pathobiology Inform Therapies for Obesity-Related Asthma

Abstract

Obesity-related asthma is associated with a high disease burden and a poor response to existent asthma therapies, suggesting that it is a distinct asthma phenotype. The proposed mechanisms that contribute to obesity-related asthma include the effects of the mechanical load of obesity, adipokine perturbations, and immune dysregulation. Each of these influences airway smooth muscle function. Mechanical fat load alters airway smooth muscle stretch affecting airway wall geometry, airway smooth muscle contractility, and agonist delivery; weight loss strategies, including medically induced weight loss, counter these effects. Among the metabolic disturbances, insulin resistance and free fatty acid receptor activation influence distinct signaling pathways in the airway smooth muscle downstream of both the M2 muscarinic receptor and the β₂ adrenergic receptor, such as phospholipase C and the extracellular signal-regulated kinase signaling cascade. Medications that decrease insulin resistance and dyslipidemia are associated with a lower asthma disease burden. Leptin resistance is best understood to modulate muscarinic receptors via the neural pathways but there are no specific therapies for leptin resistance. From the immune perspective, monocytes and T helper cells are involved in systemic pro-inflammatory profiles driven by obesity, notably associated with elevated levels of interleukin-6. Clinical trials on tocilizumab, an anti-interleukin antibody, are ongoing for obesity-related asthma. This armamentarium of therapies is distinct from standard asthma medications, and once investigated for its efficacy and safety among children, will serve as a novel therapeutic intervention for pediatric obesity-related asthma. Irrespective of the directionality of the association between asthma and obesity, airway-specific mechanistic studies are needed to identify additional novel therapeutic targets for obesity-related asthma.

Figure 1.. Effects of insulin on ASM.

Insulin-mediated dysfunction of autoinhibitory neuronal M2 muscarinic receptor results in vagally induced acetylcholine (Ach) release at neuromuscular junction, which then interacts with M3 muscarinic receptor activating pro-contractile responses in the ASM with IP3 activation and calcium mobilization. Insulin also causes activation of β₂AR-Gi-ERK/PDE4D pathway, which induces ASM contraction, while inhibition of β₂AR-Gi signaling decreases cAMP accumulation and impairs ASM relaxation. abbreviations. Ach: Acetyl choline; β2AR: Beta 2 adrenergic receptor; M2: M2 muscarinic receptor; PIP2: phosphatidylinositol (4,5) bisphosphate; PLCβ: Phospholipase C β; DAG: Diacylglycerol; IP3: Inositol trisphosphate; ASM: airway smooth muscle; ERK: extracellular signal-regulated kinase; PDE4D: Phosphodiesterase 4D; AC: adenylyl cyclase; PKA: protein kinase alpha; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate

Figure. 2.. Effects of FFAs on ASM.

FFAR1 coupling with Gβγ activates PLC/IP3/Ca2+ pathway-mediated ASM contraction (red arrows), while its coupling with Gi receptors decreases cAMP/PKA activity via adenylyl cyclase (AC) inhibition, causing c-raf inhibition. Both Gα_i and Gα_q-coupled FFAR1 activate c-raf/MEK/ERK signaling pathway, which induces HASM cell proliferation independently or through mTORC1. Gi-coupled FFAR1 activates PI3K/Akt pathways with downstream activation of mTORC1, inducing p70S6K phosphorylation and leading to HASM cell proliferation. abbreviations. ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; PKA: protein kinase alpha; MEK: Mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; mTORC1: mammalian target of rapamycin complex 1; P70S6K Ribosomal protein S6 kinase beta-1, PI3K: Phosphatidylinositol-3-kinase; PIP2: phosphatidylinositol (4,5) bisphosphate; PLCβ: Phospholipase C β; DAG: Diacylglycerol; IP3: Inositol trisphosphate;

Figure 3.. Effects of leptin on ASM.

Leptin effects on the airway are mediated by central receptors which inhibit downstream parasympathetic signaling that acts upon M3 muscarinic receptor in ASM cells. abbreviation: M3R: M3 muscarinic receptor

Figure 4.. Obesity-mediated immune perturbations and their effect on ASM.

Obesity is associated with activation of monocytes, T helper cells, preferentially of T helper 1 subset and neutrophils. Each of these cell subtypes have been associated with pulmonary function deficits found in obesity-related asthma. abbreviations. MCP1: Monocyte chemotactic protein 1; CCR2: C-C chemokine receptor type 2; SCD163: soluble cellular differentiation 163; CDC42: cell division cycle 42; IFNγ: interferon gamma; TNFα: tumor necrosis factor alpha; IL-6: Interleukin-6; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; FVC: Forced vital capacity; FEV₁: Forced expiratory volume in 1^st second; ERV: Expiratory reserve volume; FRC: Functional residual capacity; TLC: Total lung capacity; RV: Residual volume, IC: Inspiratory capacity.