Moderate chronic sleep perturbation impairs glucose and lipid homeostasis in rats.

STUDY OBJECTIVES: Sleep deprivation is a potential risk factor for metabolic diseases, including obesity and type 2 diabetes. We evaluated the impacts of moderate chronic sleep deprivation on glucose and lipid homeostasis in adult rats. METHODS: Wistar rats (both sexes) were sleep-perturbed daily for two hours at the early (06:00-08:00) and the late light cycle (16:00-18:00) five days a week (except weekends) for four weeks. RESULTS: Sleep perturbation (SP) resulted in reduced body weight gain in both sexes, associated with altered food intake and reduced adiposity. SP did not alter the short- or long-term memories or cause anxiogenic behavior. No major changes were observed in the plasma insulin, leptin, triacylglycerol, non-esterified fatty acids and blood glucose upon SP. After SP, females exhibited a transitory glucose intolerance, while males became glucose intolerant at the end of the experimental period. Male rats also developed higher insulin sensitivity at the end of the SP protocol. Morphometric analyses revealed no changes in hepatic glycogen deposition, pancreatic islet mass, islet-cell distribution, or adrenal cortex thickness in SP rats from both sexes, except for lower adipocyte size compared with controls. We did not find homogeneous changes in the relative expression of circadian and metabolic genes in muscle or hepatic tissues from the SP rats. CONCLUSIONS: Moderate chronic SP reduces visceral adiposity and causes glucose intolerance with a more pronounced impact on male rats, reinforcing the metabolic risks of exposure to sleep disturbances.

Gestational administration of vitamin D improves maternal care and prevents anxiety-like behavior in male and female Wistar rats prenatally exposed to dexamethasone.

Prenatal overexposure to glucocorticoids (GC) can lead to behavioral changes in adulthood. We aimed to explore the effects of gestational administration of vitamin D on the behavioral responses of dams and their offspring prenatally exposed to dexamethasone (DEX). Vitamin D (500UI) was given daily during the whole pregnancy (VD group). Half of the groups that received vitamin D were treated with DEX (0.1 mg/kg, VD + DEX group) daily between the 14th and 19th days of pregnancy. The corresponding control groups of progenitors were assigned (CTL and DEX groups, respectively). Maternal care and the dam's behaviors were evaluated during lactation. The offspring had developmental and behavioral parameters evaluated during lactation and at 3, 6, and 12 months of age. Gestational administration of vitamin D increased maternal care and had an anxiolytic-like effect on the dams, but the latter was blocked in DEX-treated dams. Prenatal DEX partially impaired neural development and caused an anxiety-like phenotype in the male and female offspring at 6 months, which was prevented by gestational administration of vitamin D. As well, gestational vitamin D improved memory just in the male offspring, but this response was suppressed by prenatal DEX. We concluded that gestational vitamin D could prevent anxiety-like behavior in adult male and female rats prenatally exposed to DEX, which might be, in part, a result of the maternal care improvement.

Metformin improves neurobehavioral impairments of streptozotocin-treated and western diet-fed mice: Beyond glucose-lowering effects.

Brain insulin resistance has been pointed to as a possible link between diabetes and neuropsychiatric disorders; therefore, therapeutic approaches using anti-diabetic drugs to improve insulin levels or signaling could prevent type 1 (T1D) and type 2 diabetes mellitus (T2D)-induced brain dysfunction. The present study aimed to determine whether metformin exerts beneficial effects on metabolic and neurobehavioral outcomes in the streptozotocin (STZ)-induced T1D model and western diet (WD)-induced obesity model in male Swiss mice. T1D was induced by intraperitoneal injection of STZ (50 mg/kg, for five consecutive days). The animals were then treated daily with saline or metformin (200 mg/kg/day, oral gavage), and a battery of tests recapitulating different neurobehavioral anomalies related to anxiogenic/depressive-like phenotype was conducted after 18 days. WD-induced obesity was modeled in mice by high-fat and high-fructose diet (HFFD) feeding for 15 days. In the sequence, control and diet-induced obesity mice were treated daily with saline or metformin (200 mg/kg/day), and a battery of behavioral tests was performed after 17 days. STZ injection and WD feeding induced metabolic and neurobehavioral impairments in mice. Remarkably, metformin improved the metabolic and neurobehavioral parameters in WD-induced obesity mice. Moreover, metformin ameliorated STZ-induced neurobehavioral deficits while it failed to improve the associated metabolic impairments. The beneficial effects of metformin in STZ-induced neurobehavioral impairments were not mediated by improving peripheral insulin signaling. Our results suggest that conventional diabetes treatment could be repurposed to simultaneously improve neurobehavioral symptoms and diabetes.

Antidepressant-like activity of gestational administration of vitamin D is suppressed by prenatal overexposure to dexamethasone in female Wistar rats.

Overexposure to glucocorticoids during gestation can lead to long-term mental disorders. Given the higher prevalence of depression in females, we investigated whether late gestational administration of dexamethasone could generate a depressive-like phenotype in the adult female offspring and if vitamin D could have a neuroprotective effect in this context. Pregnant rats received vitamin D (VitD, 500 IU/day) or vehicle (CTL) during gestation. Other pregnant rats received dexamethasone (Dex 0.1 mg/kg/ - 14th to the 19th gestational day) or dexamethasone + vitamin D (DexVitD). The offspring were tested for anhedonia (sucrose preference) and depressive-like behavior (forced swimming test) at postnatal months (PNM) 3, 6 and 12. Components of the serotonergic system, as well as glucocorticoids' receptors, were evaluated in the dorsal raphe nucleus at PNM 6 and 12. Prenatal vitamin D and dexamethasone increased sucrose preference at PNM 12. Prenatal vitamin D had an antidepressant-like effect at PNM 3 in rats overexposed to dexamethasone. However, at PNM 12, this effect was blunted in the DexVitD group. Prenatal dexamethasone reduced the protein content of SERT, TPH, and 5-HT1A receptors in the dorsal raphe nucleus at 6 but not at 12 PNM. The glucocorticoids' receptors expression was similar in all groups. We concluded that prenatal overexposure to dexamethasone does not change emotional behaviors in females, but it blunts the antidepressant-like effect of gestational vitamin D in an age-dependent manner. The antidepressant-like activity of vitamin D in the offspring was not related either to alterations of the serotonergic system or the glucocorticoids' receptors expression in the dorsal raphe nucleus.

Decrement in resting and insulin-stimulated soleus muscle mitochondrial respiration is an early event in diet-induced obesity in mice.

NEW FINDINGS: What is the central question of this study? What are the temporal responses of mitochondrial respiration and mitochondrial responsivity to insulin in soleus muscle fibres from mice during the development of obesity and insulin resistance? What is the main finding and its importance? Short- and long-term feeding with a high-fat diet markedly reduced soleus mitochondrial respiration and mitochondrial responsivity to insulin before any change in glycogen synthesis. Muscle glycogen synthesis and whole-body insulin resistance were present after 14 and 28 days, respectively. Our findings highlight the plasticity of mitochondria during the development of obesity and insulin resistance. ABSTRACT: Recently, significant attention has been given to the role of muscle mitochondrial function in the development of insulin resistance associated with obesity. Our aim was to investigate temporal alterations in mitochondrial respiration, H2 O2 emission and mitochondrial responsivity to insulin in permeabilized skeletal muscle fibres during the development of obesity in mice. Male Swiss mice (5-6 weeks old) were fed with a high-fat diet (60% calories from fat) or standard diet for 7, 14 or 28 days to induce obesity and insulin resistance. Diet-induced obese (DIO) mice presented with reduced glucose tolerance and hyperinsulinaemia after 7 days of high-fat diet. After 14 days, the expected increase in muscle glycogen content after systemic injection of glucose and insulin was not observed in DIO mice. At 28 days, blood glucose decay after insulin injection was significantly impaired. Complex I (pyruvate + malate) and II (succinate)-linked respiration and oxidative phosphorylation (ADP) were decreased after 7 days of high-fat diet and remained low in DIO mice after 14 and 28 days of treatment. Moreover, mitochondria from DIO mice were incapable of increasing respiratory coupling and ADP responsivity after insulin stimulation in all observed periods. Markers of mitochondrial content were reduced only after 28 days of treatment. The mitochondrial H2 O2 emission profile varied during the time course of DIO, with a reduction of H2 O2 emission in the early stages of DIO and an increased emission after 28 days of treatment. Our data demonstrate that DIO promotes transitory alterations in mitochondrial physiology during the early and late stages of insulin resistance related to obesity.