Adipose tissue inflammation and dysfunction are considered central in the pathogenesis of obesity-related dysmetabolism, but their role in the rapid metabolic recovery upon obesity reversal is less well defined. We hypothesized that changes in adipose tissue endocrine and paracrine mechanisms may support the rapid improvement of obesity-induced impairment in cellular lipid handling. C57Bl-6J mice were fed ad libitum either normal chow (NC) or high-fat diet (HFF) for 10 weeks. A dietary obesity reversal group was fed HFF for 8 weeks and then switched to NC for 2 weeks (HFF→NC). Whole-body glucose homeostasis rapidly nearly normalized in the HFF→NC mice (fasting glucose and insulin fully normalized, glucose and insulin tolerance tests reversed 82% to the NC group levels). During 2 weeks of the dietary reversal, the liver was significantly cleared from ectopic fat, and functionally, glucose production from pyruvate, alanine or fructose was normalized. In contrast, adipose tissue inflammation (macrophage infiltration and polarization) largely remained as in HFF, though obesity-induced adipose tissue macrophage lipid accumulation decreased by ~50%, and adipose tissue MAP kinase hyperactivation was reversed. Ex vivo, mild changes in adipose tissue adipocytokine secretion profile were noted. These corresponded to partial or full reversal of the excess cellular lipid droplet accumulation induced by HFF adipose tissue conditioned media in hepatoma or macrophage cells, respectively. We propose that early after initiating reversal of nutritional obesity, rapid metabolic normalization largely precedes resolution of adipose tissue inflammation. Nevertheless, we demonstrate a hitherto unrecognized contribution of adipose tissue to the rapid improvement in lipid handling by the liver and by macrophages.
Maayan Vatarescu, Sapir Bechor, Yulia Haim, Tal Pecht, Tanya Tarnovscki, Noa Slutsky, Ori Nov, Hagit Shapiro, Avishai Shemesh, Angel Porgador, Nava Bashan, and Assaf Rudich
Kanta Kon, Hiroshi Tsuneki, Hisakatsu Ito, Yoshinori Takemura, Kiyofumi Sato, Mitsuaki Yamazaki, Yoko Ishii, Masakiyo Sasahara, Assaf Rudich, Takahiro Maeda, Tsutomu Wada, and Toshiyasu Sasaoka
Disrupted sleep is associated with increased risk of type 2 diabetes. Central actions of orexin, mediated by orexin-1 and orexin-2 receptors, play a crucial role in the maintenance of wakefulness; accordingly, excessive activation of the orexin system causes insomnia. Resting-phase administration of dual orexin receptor antagonist (DORA) has been shown to improve sleep abnormalities and glucose intolerance in type 2 diabetic db/db mice, although the mechanism remains unknown. In the present study, to investigate the presence of functional link between sleep and glucose metabolism, the influences of orexin antagonists with or without sleep-promoting effects were compared on glucose metabolism in diabetic mice. In db/db mice, 2-SORA-MK1064 (an orexin-2 receptor antagonist) and DORA-12 (a DORA) acutely improved non-rapid eye movement sleep, whereas 1-SORA-1 (an orexin-1 receptor antagonist) had no effect. Chronic resting-phase administration of these drugs improved glucose intolerance, without affecting body weight, food intake, locomotor activity and energy expenditure calculated from O2 consumption and CO2 production. The expression levels of proinflammatory factors in the liver were reduced by 2-SORA-MK1064 and DORA-12, but not 1-SORA-1, whereas those in the white adipose tissue were reduced by 1-SORA-1 and DORA-12 more efficiently than 2-SORA-MK1064. When administered chronically at awake phase, these drugs caused no effect. In streptozotocin-induced type 1-like diabetic mice, neither abnormality in sleep–wake behavior nor improvement of glucose intolerance by these drugs were observed. These results suggest that both 1-SORA-type (sleep-independent) and 2-SORA-type (possibly sleep-dependent) mechanisms can provide chronotherapeutic effects against type 2 diabetes associated with sleep disturbances in db/db mice.