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CO2 as a Potential Obesogen: A Gas That Will Stick to Your Ribs.

Historically considered a simple storage depot for caloric excess, white adipose tissue (WAT) is now understood to be a complex, multicellular endocrine and immune organ that regulates whole-body insulin sensitivity, inflammation, and cardiovascular function (1, 2). Adipogenesis, the process in WAT through which mesenchymal precursor cells are progressively differentiated into mature lipid-laden, insulin-responsive adipocytes, involves sequential waves of transcription factors that cooperatively remodel chromatin and reprogram gene expression (3, 4). Chief among adipogenic transcription factors is peroxisome proliferatoractivated receptor (PPAR)g, a master regulator that is both necessary and sufficient for adipogenesis (3). During obesity, excessive expansion of subcutaneous WAT, which is quantitatively the largest adipose depot in humans, leads to increases in ectopic (i.e., visceral) adipose deposition and to WAT dysfunction (infiltration of proinflammatory macrophages, abnormal adipokine and free fatty acid secretion, and insulin resistance) (5). It is generally thought that adipocyte hypertrophy (cellular lipid overload) drives these untoward effects of obesity, whereas PPARg-dependent adipocyte hyperplasia (i.e., recruitment of adipocytes through differentiation of precursors) may be protective (5). Although the issue is somewhat controversial, tissue hypoxia is generally thought to be an important driver of cellular dysfunction in WAT during obesity (6). Reciprocal interactions between obstructive sleep apnea (OSA) and obesity may conspire in this regard to accelerate metabolic disarray. Obesity is a major risk factor for OSA. On the other hand, OSA is also associated with metabolic syndrome (7), perhaps in part by exacerbating WAT hypoxia and consequent dysfunction (6). In recent years, hypercapnia, another metabolic consequence of OSA and chronic lung disease, has been shown to impact the function of epithelial, immune, and other cell types through effects on cell signaling (8). Whether adipocytes are responsive to changes in local CO2 remains unclear. In the this issue of the Journal, Kikuchi and colleagues (pp. 570–580) show that elevated ambient CO2 (i.e., 10% or 7.5% compared with 5%) dose dependently accelerates differentiation of human subcutaneous and visceral preadipocytes in culture (i.e., adipogenesis) (9). This held true under normoxia and hypoxia, under neutral (pH 7.4) and acidic (pH 7.1) extracellular conditions, and during sustained, intermittent (30 min every h, 6 h/d, for 4 d), or transient (6 continuous h/d for 4 d) hypercapnia. By contrast, hypercapnia did not impact adipocyte hypertrophy. The authors provide evidence that CO2 drives adipogenesis through a pathway involving soluble adenylyl cyclase (sAC)-dependent production of cyclic adenosine monophosphate (cAMP). Specifically, hypercapnia-induced cAMP activates cAMP response element binding protein (CREB), in turn promoting activation of the proadipogenic transcription factors PPARg and CCAAT/enhancer binding protein b. The authors also provide evidence that two additional cAMP effectors that have previously been implicated in adipogenesis, protein kinase A and exchanger protein directly activated by cAMP, are also activated by hypercapnia in a sAC-dependent manner, and also contribute to hypercapnia-induced adipogenesis. With regard to translational relevance, the authors propose that this pathway may put a deleterious positive feedback loop in motion during OSA: hypercapnia accelerates adipogenesis, increasing fat mass and hypoventilation, thereby exacerbating hypercapnia. This interesting report adds preadipocytes to the growing list of cell types that functionally sense CO2. sAC, in tandem with carbonic anhydrase, an enzyme that catalyzes interconversion of CO2 and HCO3 , has been shown to serve as a biosensor for CO2 in other cell types, activating protein kinase A, CREB, and other cAMP effectors (10, 11). Although the cause of its activation is ambiguous, sAC may in fact be activated in response to carbonic anhydrasecatalyzed intracellular HCO3 , rather than directly by CO2 itself (10, 11). Reports that carbonic anhydrase isoforms are dramatically induced during adipocyte differentiation (12) and that carbonic anhydrase III regulates adipocyte PPARg and adipogenesis (13) may intriguingly suggest that differentiating preadipocytes are tuned to be either especially sensitive to or buffered against changes in local CO2/HCO3 . Given that cAMP can induce both adipogenesis and adipocyte lipolysis (14), it remains to be seen how or whether intracellular compartmentalization of hypercapnia-induced cAMP in adipocytes couples specific cAMP effectors to cellular functions, and whether this may vary in different tissue contexts. The report by Kikuchi and colleagues has several notable strengths. It uses primary human preadipocytes from different anatomic locations rather thanmurine cell lines, and rigorously shows that the CO2 effect is dependent on concentration and independent of extracellular acidosis and oxygen conditions. It also confirms the expression of sAC in human visceral and subcutaneous WAT, and convincingly ties sAC-dependent hypercapnia responses into a canonical adipogenic signaling cascade established by the field. Key questions not addressed by the report include whether CO2 also biases mesenchymal precursor cells toward preadipocyte commitment, and whether CO2 impacts PPARg-dependent adipogenesis in brown adipose tissue (a thermogenic, energyconsuming type of adipose), and PPARg-dependent browning of WAT adipocytes (1, 6). Another key question is whether hypercapnia induces adipogenesis in vivo. Appropriately designed rodent models may allow investigators to determine not only