Oxytocin has been revealed to work for anxiety suppression and anti-stress as well as for psychosocial behavior and reproductive functions. Oxytocin neurons are activated by various stressful stimuli. The oxytocin receptor is widely distributed within the brain, and oxytocin that is released or diffused affects behavioral and neuroendocrine stress responses. On the other hand, there has been an increasing number of reports on the role of oxytocin in allostasis and resilience. It has been shown that oxytocin maintains homeostasis, shifts the set point for adaptation to a changing environment (allostasis) and contributes to recovery from the shifted set point by inducing active coping responses to stressful stimuli (resilience). Recent studies have suggested that oxytocin is also involved in stress-related disorders, and it has been shown in clinical trials that oxytocin provides therapeutic benefits for patients diagnosed with stress-related disorders. This review includes the latest information on the role of oxytocin in stress responses and adaptation.

Oxytocin (OXT) and OXT receptor (OXTR) have been implicated in the regulation of energy homeostasis, but the detailed mechanism is still unclear. We recently showed late-onset obesity and impaired cold-induced thermogenesis in male OXTR knockout (Oxtr^−/−) mice. Here we demonstrate that the OXTR in the hypothalamus has important functions in thermoregulation. Male Oxtr^−/− mice failed to maintain their body temperatures during exposure to a cold environment. Oxtr^−/− mice also showed decreased neuronal activation in the thermoregulatory hypothalamic region during cold exposure. Normal cold-induced thermogenesis was recovered in Oxtr^−/− mice by restoring OXTR to the hypothalamus with an adeno-associated virus-Oxtr vector. In addition, brown adipose tissue (BAT) in Oxtr^−/− mice contained larger lipid droplets in both 10- and 20-week-old compared with BAT from age-matched Oxtr^+/+ control mice. In BAT, the expression level of β3-adrenergic receptor at normal temperature was lower in Oxtr^−/− mice than that in control mice. In contrast, α2A-adrenergic receptor expression level was higher in BAT from Oxtr^−/− mice in both normal and cold temperatures. Because β3- and α2A-adrenergic receptors are known to have opposite effects on the thermoregulation, the imbalance of adrenergic receptors is suspected to affect this dysfunction in the thermoregulation. Our study is the first to demonstrate that the central OXT/OXTR system plays important roles in the regulation of body temperature homeostasis.

Early‐life experience influences social and emotional behaviour in adulthood. Affiliative tactile stimuli in early life facilitate the development of social and emotional behaviour, whereas early‐life adverse stimuli have been shown to increase the risk of various diseases in later life. On the other hand, oxytocin has been shown to have organizational actions during early‐life stages. However, the detailed mechanisms of the effects of early‐life experience and oxytocin remain unclear. Here, we review the effects of affiliative tactile stimuli during the neonatal period and neonatal oxytocin treatment on the activity of the oxytocin–oxytocin receptor system and social or emotional behaviour in adulthood. Both affiliative tactile stimuli and early‐life adverse stimuli in the neonatal period acutely activate the oxytocin–oxytocin receptor system in the brain but modulate social behaviour and anxiety‐related behaviour apparently in an opposite direction in adulthood. Accumulating evidence suggests that affiliative tactile stimuli and exogenous application of oxytocin in early‐life stages induce higher activity of the oxytocin–oxytocin receptor system in adulthood, although the effects are dependent on experimental procedures, sex, dosages and brain regions examined. On the other hand, early‐life stressful stimuli appear to induce reduced activity of the oxytocin–oxytocin receptor system, possibly leading to adverse actions in adulthood. It is possible that activation of a specific oxytocin system can induce beneficial actions against early‐life maltreatments and thus could be used for the treatment of developmental psychiatric disorders.

Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A), an enzyme that hydrolyzes glycosphingolipids in lysosome. Accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in tissues induces cellular dysfunction leading to multi-organ disorder. Gene therapy is a promising strategy that can overcome these problems, and virus vectors such as adeno-associated virus (AAV) have been used for study on gene therapy. We used human Gb3 synthetase-transgenic (TgG3S)/α-Gal A knockout (GLAko) mice. TgG3S/GLAko mice have elevated Gb3 accumulation in the major organs compared to GLAko mice, which have been widely used as a model for FD. At the age of 6 weeks, male TgG3S/GLAko were injected with 2 × 1012 vector genome AAV9 vectors containing human α-Gal A cDNA. Eight weeks after intravenous injection of AAV, α-Gal A enzymatic activity was elevated in the plasma, heart, and liver of TgG3S/GLAko mice to levels corresponding to 224%, 293%, and 105% of wild-type (WT), respectively. Gb3 amount 8 weeks after AAV injection in the heart and liver of this group was successfully reduced to levels corresponding to 16% and 3% of untreated TgG3S/GLAko mice. Although the brain and kidney of AAV9-treated TgG3S/GLAko mice showed no significant increases in α-Gal A activity, Gb3 amount was smaller than untreated littermates (48% and 44%, respectively). In this study, systemic AAV administration did not show significant extension of the lifespan of TgG3S/GLAko mice compared to the untreated littermates. The timing of AAV injection, capsid choice, administration route, and injection may be important to achieve sufficient expression of α-Gal A in the whole body for the amelioration of lifespan.

Background: Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α‐galactosidase A (α‐Gal A) encoded by the GLA gene. The symptoms of FD occur as a result of the accumulation of globotriaosylceramide (Gb3), comprising a substrate of α‐Gal A, in the organs. Adeno‐associated virus (AAV)‐mediated gene therapy is a promising treatment for FD.Methods: α‐Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 10¹¹ viral genomes [vg]) or AAV9 (1 × 10¹¹ or 2 × 10¹² vg) vectors carrying human GLA (AAV‐hGLA), and plasma, brain, heart, liver and kidney were tested for α‐Gal A activity. The vector genome copy numbers (VGCNs) and Gb3 content in each organ were also examined.Results: The plasma α‐Gal A enzymatic activity was three‐fold higher in the AAV9 2 × 10¹² vg group than wild‐type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 10¹² vg group, the level of α‐Gal A expression was high in the heart and liver, intermediate in the kidney, and low in the brain. VGCNs in the all organs of the AAV9 2 × 10¹² vg group significantly increased compared to the phosphate‐buffered‐saline (PBS) group. Although Gb3 in the heart, liver and kidney of the AAV9 2 × 10¹² vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced.Conclusions: Systemic injection of AAV9‐hGLA resulted in α‐Gal A expression and Gb3 reduction in the organs of GLAko mice. To expect a higher expression of α‐Gal A in the brain, the injection dosage, administration route and the timing of injection should be reconsidered.

During obesity, tissue macrophages increase in number and become proinflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient Lep^ob/ob mice with mice lacking the Lpl gene in myeloid cells (Lpl^m−/m−) to generate Lpl^m−/m−;Lep^ob/ob mice. We found the weight of perigonadal white adipose tissue (WAT) was increased in Lpl^m−/m−;Lep^ob/ob mice compared with Lep^ob/ob mice due to substantial accumulation of both adipose tissue macrophages and collagen that surrounded necrotic adipocytes. In the fibrotic epidydimal WAT of Lpl^m−/m−;Lep^ob/ob mice, we observed an increase in collagen VI and high mobility group box 1, while α-smooth muscle cell actin, a marker of myofibroblasts, was almost undetectable, suggesting that the adipocytes were the major source of the collagens. Furthermore, the adipose tissue macrophages from Lpl^m−/m−;Lep^ob/ob mice showed increased expression of genes related to fibrosis and inflammation. In addition, we determined Lpl^m−/m−;Lep^ob/ob mice were more hypertriglyceridemic than Lep^ob/ob mice. Lpl^m−/m−;Lep^ob/ob mice also showed slower weight gain than Lep^ob/ob mice, which was primarily due to reduced food intake. In conclusion, we discovered that the loss of myeloid Lpl led to extensive fibrosis of perigonadal WAT and hypertriglyceridemia. In addition to illustrating an important role of macrophage LPL in regulation of circulating triglyceride levels, these data show that macrophage LPL protects against fibrosis in obese adipose tissues.