Chitinase 3–like-1 Regulates Both Visceral Fat Accumulation and Asthma-like Th2 Inflammation

Abstract

Rationale: Obesity, especially truncal obesity, is a risk factor for asthma incidence, prevalence, and severity. Chitinase 3-like-1 (Chi3l1) is an evolutionarily conserved moiety that plays a critical role in antipathogen and Th2 responses. However, the mechanisms that underlie the association between asthma and obesity and the role(s) of Chi3l1 in fat accumulation have not been defined.Objectives: To determine whether Chi3l1 is regulated by a high-fat diet (HFD) and simultaneously plays an important role(s) in the pathogenesis of asthma and obesity.Methods: We evaluated the regulation of Chi3l1 by an HFD and Th2 inflammation. We also used genetically modified mice to define the roles of Chi3l1 in white adipose tissue (WAT) accumulation and Th2 inflammation and blockers of sirtuin 1 (Sirt1) to define its roles in these responses. Finally, the human relevance of these findings was assessed with a case-control study involving obese and lean control subjects and those with asthma. Measurements and MainResults: These studies demonstrate that an HFD and aeroallergen challenge augment the expression of WAT and pulmonary Chi3l1. Chi3l1 also played a critical role in WAT accumulation and lung Th2 inflammation. In addition, Chi3l1 inhibited Sirt1 expression, and the deficient visceral fat and Th2 responses in Chi3l1 null mice were reversed by Sirt1 inhibition. Finally, serum and sputum Chi3l1 were positively associated with truncal adiposity, and serum Chi3l1 was associated with persistent asthma and low lung function in obese subjects with asthma.Conclusions: Chi3l1 is induced by an HFD and Th2 inflammation, and simultaneously contributes to the genesis of obesity and asthma.

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

“…It is likely that common metabolic pathways contribute to both the development of allergic airway disease and increased visceral obesity. For example, Chitinase 3-like-1 is involved in the development of allergic responses and also in the development of visceral obesity, possibly through effects on genes involved in metabolism (49). Metabolism is a critical regulator of immune cell function; increased cellular metabolism is required to fuel the demands of immune mediator biosynthesis and cell division (50).…”

A Common Pathway to Obesity and Allergic Asthma

“…Its protein product (Chi3l1; also known as YKL-40, BRP-39, and HC gp-39) is associated with risk for asthma and lung function impairment and is involved in the development of Th2 responses, allergic airway inflammation, and methacholine hyperresponsiveness (10). The current article suggests that Chi3l1 is also involved in the pathogenesis of obesity (9). Mice genetically deficient in Chi3l1 developed less visceral obesity and had smaller adipocytes, producing lower levels of cytokines, than wild-type controls.…”

“…In this issue of the Journal, Ahangari and colleagues (pp. 746-757) force us to rethink this question (9), as debating whether obesity or asthma comes first ignores a third possibility: that common pathways might promote both allergic airway disease and the development of visceral obesity.…”

Asthma 2015: The Year in Review

“…As an example, a regulatory peptide, chitinase 3-like 1, was shown to play a direct role in the Th2 response associated with asthma and also in the development of truncal obesity. 1 Obesity-associated asthma is not thought to be a distinct endotype. Children who are overweight and obese with early onset asthma tend to have poorer asthma control, with a fairly distinct pattern of symptoms, including greater dyspnea, increased use of short-acting ␤ 2 agonists like albuterol, less methacholine responsiveness (ie, less bronchial hyper-responsiveness), lower exhaled nitric oxide, and less cough.…”

“…Between January 1,2015, and the end of October, there were Ͼ6,500 peer-reviewed papers listed in PubMed on asthma. Of necessity, those that have been selected for inclusion represent just a few of those that have caught this reviewer's interest.…”