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  • Notably both circulating adiponectin and adipsin were equall

    2024-02-20

    Notably, both circulating adiponectin and adipsin were equally diminished by about 50% in Arfrp1 mice consistent with several studies reporting overlapping trafficking routes for their secretion from 3T3-L1 vorapaxar which was strikingly inhibited upon ablation of TfR-positive endosomes [18,26,33]. In agreement with an unaffected leptin secretion (Figure 1A,E), post-Golgi traffic of leptin was shown to occur independently of intact endosomal compartments as their inactivation did not compromise leptin release from 3T3-L1 or primary rat adipocytes [18]. The fact that deletion of Arfrp1 reduces the plasma levels of adiponectin and adipsin could indicate that the observed phenotype is the consequence of both adipokines. However, the Spiegelman group recently reassessed the metabolic role of adipsin [34] showing that adipsin has an impact on sustaining insulin production and/or secretion particularly under conditions of diet-induced obesity. As mice in the present study received a standard diet and additionally showed no obvious phenotype concerning plasma insulin levels, further investigations focused on adiponectin. Interestingly, the previously generated conditional fat-specific Arfrp1 knockout mouse did not exhibit reduced plasma adiponectin levels, as observed in the current study. However, conditional knockout mice failed to develop functional WAT and only displayed residual BAT, still expressing a considerable amount of Arfrp1, which might represent the exclusive adiponectin source in these mice [10]. Different mouse models of genetic adiponectin ablation demonstrated a selective hepatic insulin resistance without any impairments of insulin sensitivity in skeletal muscle, even under standard diet-fed conditions [25,35,36]. In this context, hypoadiponectinemia was shown to reduce hepatic IRS-2 expression [20,31]. In particular, adiponectin transiently increases macrophage-derived plasma IL-6 levels, which, in turn, activate hepatic STAT3 to induce hepatic IRS-2 expression and enhance insulin sensitivity in the liver [20]. Intriguingly, IRS-2 largely determines insulin signaling in the liver during fasting, thereby substantially controlling hepatic glucose production via gluconeogenesis [21]. Following defective endosomal-mediated exocytosis, cell surface exposure of the TfR was substantially diminished in Arfrp1-depleted HeLa cells (Figure 3E,F). Similarly, the insulin receptor was less abundant at the plasma membrane in primary adipocytes (Figure 4A,B) and 3T3-L1 cells (Figure 4E,F) deficient of Arfrp1. After binding of insulin to its receptor and internalization, receptor-ligand complexes are directed for either lysosomal degradation, a way of downregulating signal reception, or receptors are sorted for reinsertion into the plasma membrane [37,38]. In this context, it was demonstrated that prevention of insulin receptor recycling resulted in an accelerated shunting to a degradative pathway, thereby reducing the amount of total cellular receptors [21]. Indeed, 10-week-old Arfrp1 mice revealed substantially diminished protein levels of the mature receptor in gonWAT lysates, suggesting that impaired re-exposure at the cell surface, as assessed by lower plasma membrane abundance in adipocytes from 7-week-old Arfrp1 mice, was accompanied by enhanced receptor degradation (Figure 4C,D). As expected, the insulin receptor surface deficiency resulted in reduced adipose insulin sensitivity (Figure 5A–C). By promoting triglyceride synthesis and inhibiting lipolysis, insulin signaling enhances overall lipid storage in adipocytes. Consistently, adipose tissue explants from Arfrp1 mice exhibited an increased basal lipolytic rate as well as impaired insulin-mediated suppression of isoproterenol-stimulated lipolysis (Figure 5G). Insufficiently repressed lipolysis consequently associated with an impaired hypertrophic growth of adipose tissue depots in Arfrp1 mice (Figure 5J). Collectively, these findings demonstrate the requirement of ARFRP1 for mature adipocytes to maintain proper insulin action, thereby determining adipose tissue mass.