The molecular mechanisms linking obstructive sleep apnea syndrome (OSA) to obesity and the development of metabolic diseases are still poorly understood. The role of hypoxia (a characteristic feature of OSA) in excessive fat accumulation has been proposed. The present study investigated the possible effects of hypoxia (4% oxygen) on de novo lipogenesis by tracking the major carbon sources in differentiating 3T3-L1 adipocytes. Gas-permeable cultuware was employed to cultivate 3T3-L1 adipocytes in hypoxia (4%) for 7 or 14 days of differentiation. We investigated the contribution of glutamine, glucose or acetate using 13C or 14C labelled carbons to the newly synthesized lipid pool, changes in intracellular lipid content after inhibiting citrate- or acetate-dependent pathways and gene expression of involved key enzymes. The results demonstrate that, in differentiating adipocytes, hypoxia decreased the synthesis of lipids from glucose (44.1 ± 8.8 to 27.5 ± 3.0 pmol/mg of protein, p < 0.01) and partially decreased the contribution of glutamine metabolized through the reverse tricarboxylic acid cycle (4.6% ± 0.2-4.2% ± 0.1%, p < 0.01). Conversely, the contribution of acetate, a citrate- and mitochondria-independent source of carbons, increased upon hypoxia (356.5 ± 71.4 to 649.8 ± 117.5 pmol/mg of protein, p < 0.01). Further, inhibiting the citrate- or acetate-dependent pathways decreased the intracellular lipid content by 58% and 73%, respectively (p < 0.01) showing the importance of de novo lipogenesis in hypoxia-exposed adipocytes. Altogether, hypoxia modified the utilization of carbon sources, leading to alterations in de novo lipogenesis in differentiating adipocytes and increased intracellular lipid content.

• MeSH
• Acetates * metabolism   pharmacology   MeSH
• Cell Differentiation * drug effects   MeSH
• 3T3-L1 Cells * MeSH
• Citric Acid Cycle MeSH
• Glucose * metabolism   MeSH
• Glutamine * metabolism   MeSH
• Cell Hypoxia MeSH
• Lipids biosynthesis   MeSH
• Lipogenesis * drug effects   MeSH
• Lipid Metabolism drug effects   MeSH
• Mice MeSH
• Adipocytes * metabolism   drug effects   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetates * MeSH
• Glucose * MeSH
• Glutamine * MeSH
• Lipids MeSH

The molecular mechanisms linking obstructive sleep apnea (OSA) with type 2 diabetes mellitus (T2DM) remain unclear. This study investigated the effect of OSA on skeletal muscle lipid oxidation in nondiabetic controls and in type 2 diabetes (T2DM) patients. Forty-four participants matched for age and adiposity were enrolled: nondiabetic controls (control, n = 14), nondiabetic patients with severe OSA (OSA, n = 9), T2DM patients with no OSA (T2DM, n = 10), and T2DM patients with severe OSA (T2DM + OSA, n = 11). A skeletal muscle biopsy was performed; gene and protein expressions were determined and lipid oxidation was analyzed. An intravenous glucose tolerance test was performed to investigate glucose homeostasis. No differences in lipid oxidation (178.2 ± 57.1, 161.7 ± 22.4, 169.3 ± 50.9, and 140.0 ± 24.1 pmol/min/mg for control, OSA, T2DM, and T2DM+OSA, respectively; p > 0.05) or gene and protein expressions were observed between the groups. The disposition index, acute insulin response to glucose, insulin resistance, plasma insulin, glucose, and HBA1C progressively worsened in the following order: control, OSA, T2DM, and T2DM + OSA (p for trend <0.05). No association was observed between the muscle lipid oxidation and the glucose metabolism variables. We conclude that severe OSA is not associated with reduced muscle lipid oxidation and that metabolic derangements in OSA are not mediated through impaired muscle lipid oxidation.

• Keywords
• IVGTT, free fatty acids, glucose intolerance, hypoxia, lipid utilization, muscle metabolism, obstructive sleep apnea, type 2 diabetes mellitus,
• MeSH
• Diabetes Mellitus, Type 2 * complications   metabolism   MeSH
• Glucose metabolism   MeSH
• Insulin Resistance * MeSH
• Insulins * MeSH
• Humans MeSH
• Lipids MeSH
• Sleep Apnea, Obstructive * metabolism   MeSH
• Polysomnography MeSH
• Muscles metabolism   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Glucose MeSH
• Insulins * MeSH
• Lipids MeSH

Obstructive sleep apnoea (OSA) is associated with type 2 diabetes mellitus (T2DM). However, mechanisms mediating association between these two conditions remain unclear. This study investigated, whether the OSA-associated changes in adipose tissue lipolysis might contribute to impaired glucose homeostasis in patient with T2DM. Thirty-five matched subjects were recruited into three groups: T2DM + severe OSA (T2DM + OSA, n = 11), T2DM with mild/no OSA (T2DM, n = 10) and healthy controls (n = 14). Subcutaneous abdominal adipose tissue microdialysis assessed spontaneous, epinephrine- and isoprenaline-stimulated lipolysis. Glucose metabolism was assessed by intravenous glucose tolerance test. Spontaneous lipolysis was higher in the T2DM + OSA compared with the T2DM (60.34 ± 23.40 vs. 42.53 ± 10.16 μmol/L, p = 0.013), as well as epinephrine-stimulated lipolysis (236.84 ± 103.90 vs. 167.39 ± 52.17 µmol/L, p < 0.001). Isoprenaline-stimulated lipolysis was unaffected by the presence of OSA (p = 0.750). The α2 anti-lipolytic effect was decreased in T2DM + OSA by 59% and 315% compared with T2DM and controls (p = 0.045 and p = 0.007, respectively). The severity of OSA (AHI) was positively associated with spontaneous (p = 0.037) and epinephrine-stimulated (p = 0.026) lipolysis. The α2-adrenergic anti-lipolytic effect (p = 0.043) decreased with increasing AHI. Spontaneous lipolysis was positively associated with Insulin resistance (r = 0.50, p = 0.002). Epinephrine-stimulated lipolysis was negatively associated with the Disposition index (r = - 0.34, p = 0.048). AHI was positively associated with Insulin resistance (p = 0.017) and negatively with the Disposition index (p = 0.038). Severe OSA in patients with T2DM increased adipose tissue lipolysis, probably due to inhibition of the α2-adrenergic anti-lipolytic effect. We suggest that dysregulated lipolysis might contribute to OSA-associated impairments in insulin secretion and sensitivity.

• MeSH
• Epinephrine administration & dosage   MeSH
• Diabetes Mellitus, Type 2 complications   epidemiology   metabolism   pathology   MeSH
• Glucose metabolism   MeSH
• Homeostasis physiology   MeSH
• Insulin metabolism   MeSH
• Insulin Resistance physiology   MeSH
• Isoproterenol administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipolysis drug effects   genetics   MeSH
• Sleep Apnea, Obstructive complications   epidemiology   metabolism   pathology   MeSH
• Aged MeSH
• Adipose Tissue drug effects   metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Epinephrine MeSH
• Glucose MeSH
• Insulin MeSH
• Isoproterenol MeSH