Hypercapnia Accelerates Adipogenesis: A Novel Role of High CO₂ in Exacerbating Obesity

Abstract

Obesity is a major risk factor for the development of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS), which manifest as intermittent hypercapnia and sustained plus intermittent hypercapnia, respectively. In this study, we investigated whether CO affects adipocyte differentiation (adipogenesis) and maturation (hypertrophy). Human visceral or subcutaneous preadipocytes were grown to confluence and then induced to differentiate to adipocytes under hypocapnia, normocapnia, and hypercapnia with or without hypoxia. Adipogenesis was also induced under intermittent or sustained hypercapnia. Differentiated adipocytes were maintained to maturity under normocapnia or hypercapnia. Our main findings are as follows: (1) hypercapnia accelerated adipogenesis in visceral and subcutaneous preadipocytes, whereas hypocapnia inhibited adipogenesis; (2) hypercapnia did not affect adipocyte hypertrophy; (3) hypercapnia-accelerated adipogenesis was independent of extracellular acidosis, oxygen concentration, or either intermittent or sustained exposure to high CO; and (4) the mechanisms underlying hypercapnia-accelerated adipogenesis involved increased production of cyclic adenosine monophosphate (cAMP) via soluble adenylyl cyclase, leading to the activation of protein kinase A and exchanger protein directly activated by cAMP, which, in turn, activated proadipogenic transcription factors, such as cAMP response element binding protein, CCAAT/enhancer binding protein β, and peroxisome proliferator-activated receptor γ. This study reveals a novel role of high CO in promoting adipogenesis, which provides mechanistic clues to a pathoetiological interaction between OSA/OHS and obesity. Our data suggest a vicious cycle of disease progression via the following mechanism: OSA/OHS → hypoventilation → hypercapnia → increased adipogenesis → increased fat mass → exacerbated OSA/OHS.

Sleep-disordered breathing, circulating exosomes, and insulin sensitivity in adipocytes

“…Accordingly, the beneficial effects of CPAP in our OHS cohort could have resulted from the improvements in both hypoxia and hypercapnia, and therefore future murine studies may need to explore both the isolated and combined role of hypercapnia to exosome biological properties in adipocytes. 69 There are several additional limitations in this study that merit discussion. First, the untreated OSA group is not entirely comparable to the OHS group, i.e., lower BMI, lower glucose and insulin levels, and slightly higher adiponectin than OHS at baseline.…”

“…This study provides a compelling proof of concept illustrating that exosomes derived from OHS patients following CPAP treatment improved insulin sensitivity in naïve human adipocytes, while absence of any therapeutic intervention, which would be unethical in OHS but is deemed acceptable in the less severe OSA cases illustrates the absence of any temporal changes in the functional properties of circulating exosomes. In addition, OHS is a clinical entity characterized by the coexistence of obesity and hypoxia and hypercapnia during wakefulness, with a recent study reporting that hypercapnia promotes adipogenesis in human adipocytes 69 . Accordingly, the beneficial effects of CPAP in our OHS cohort could have resulted from the improvements in both hypoxia and hypercapnia, and therefore future murine studies may need to explore both the isolated and combined role of hypercapnia to exosome biological properties in adipocytes.…”

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

“…Besides promoting CREB activity, sAC also regulates several other transcription factors. For example, sAC supports hypercapnia-accelerated adipogenesis via the activation of pro-adipogenic transcription factors, such as CREB, CCAAT/enhancer binding protein ß and proliferator-activated receptor γ [ 85 ]. Similarly, sAC-PKA-dependent phosphorylation, and thus the activation of transcription factor 4, is required for brain development [ 86 ].…”

MECHANISMS OF ENDOCRINOLOGY: Mechanisms of disease: the endocrinology of obstructive sleep apnoea

“…In addition, disruption of sleep architecture (suppression of SWS as happens in OSA) without affecting sleep duration in young healthy men, increased hunger for high-calorie food in the afternoon and evening (50). OSA could also contribute to increased fat mass by activation of the HPA axis and increased cortisol secretion and by hypercapnia-induced adipogenesis (51,52). However, despite the above-mentioned plausible mechanisms, epidemiological evidence for an impact of OSA on weight longitudinally is lacking.…”