Sex Differences in Infant Rhesus Macaque Separation–Rejection Vocalizations and Effects of Prenatal Androgens

Infant and juvenile rhesus macaques exhibit many sexually dimorphic behaviors, including rough and tumble play, mounting, and time spent with nonmother females. This study investigated sex differences in infant rhesus monkey separation–rejection vocalizations (SRVs), and the effects of altering the prenatal hormone environment on these differences. Pregnant females received exogenous androgen (testosterone enanthate), an androgen antagonist (flutamide), or vehicle injections for 30 or 35 days during the second (early) or third (late) trimester of pregnancy. Control females used a greater percentage of coos and arched screams than did control males. In contrast, males used a greater percentage of geckers and noisy screams than did females. Females also had longer SRV bouts, used more calls, and used more types of vocalizations than did males. Mothers were more likely to respond to the SRVs of male infants than to the SRVs of female infants. Prenatal flutamide treatment early in gestation reduced the likelihood that mothers would respond to their male offspring, but prenatal androgen treatment had no effect on response rates of mothers to female offspring. Early, but not late, androgen treatment produced females who vocalized in a male-typical manner. Similarly, early flutamide treatment produced males who displayed more female-typical SRVs. Late flutamide treatments of females produced as much masculinization of SRVs as did early androgen treatment in females. These results demonstrate sex differences in highly emotional vocalizations in infant rhesus macaques and provide evidence that the timing and form of prenatal hormonal exposure influence such vocalizations.     

Sex hormone-binding globulin overexpression protects against high-fat diet-induced obesity in transgenic male mice

Obese subjects of all ages and sex have reduced plasma SHBG levels. Whether these low plasma SHBG levels play a role in obesity development is unknown. In the present work we wanted to explore if SHBG overexpression could prevent obesity development induced by high fat diet (HFD). To do so, we fed humanized SHBG transgenic male mice and their wild-type littermates with control diet (CD) or HFD over the course of 8 weeks. The results showed that SHBG overexpression protected against body weight gain and fat accumulation induced by HFD. In addition, SHBG overexpression also abrogated the increase in insulin, leptin and resistin levels, as well as the reduction in adiponectin, induced by HFD. Mechanistically, the SHBG protection against HFD-induced obesity was achieved by stimulating lipolysis in white adipose tissue. Furthermore, we have demonstrated the SHBG cell-autonomous effect using human primary visceral adipocytes. Taking together, our results demonstrate that SHBG overexpression protects against diet-induced obesity and improves the metabolic profile of male mice fed a HFD diet.     

Sex chromosome complement affects multiple aspects of reversal-learning task performance in mice

Determining the mechanisms by which the sex-chromosome complement (SCC) affects learning, attention, and impulsivity has implications for observed sex differences in prevalence, severity, and prognosis of psychiatric/neurodevelopmental disorders and syndromes associated with sex-chromosome aneuploidy. Here, Four Core Genotypes (FCG) mice were evaluated in order to assess the separable and/or interacting effects of gonads (testes vs. ovaries) and their secretions and/or SCC (XX vs. XY) acting via non-gonadal mechanisms on behavior. We tested FCG mice on a reversal-learning task that enables the quantification of aspects of learning, attention and impulsivity. Across testing phases (involving the initial acquisition of a spatial discrimination and subsequent reversal learning), overall error rate was larger in XY compared with XX mice. Although XX and XY groups did not differ in the total number of trials required in order to reach a preset performance criterion, analyses of reversal error types showed more perseverative errors in XY than XX mice, with no difference in regressive errors. Additionally, prepotent-response latencies during the reversal phase were shorter in XY males, as compared with both XX gonadal males and females of either SCC, and failures to sustain the observing response were more frequent in XY mice than XX mice during the acquisition phase. These results indicate that SCC affects the characteristic pattern of response selection during acquisition and reversal performance without affecting the overall learning rate. More broadly, these results show direct effects of the SCC on cognitive processes that are relevant to psychiatric/neurodevelopmental disorders and syndromes associated with sex-chromosome aneuploidies.     

Effects of selenium supplementation on diet-induced obesity in mice with a disruption of the selenocysteine lyase gene

BACKGROUNDThe amino acid selenocysteine (Sec) is an integral part of selenoproteins, a class of proteins mostly involved in strong redox reactions. The enzyme Sec lyase (SCLY) decomposes Sec into selenide allowing for the recycling of the selenium (Se) atom via the selenoprotein synthesis machinery. We previously demonstrated that disruption of the Scly gene (Scly KO) in mice leads to the development of obesity and metabolic syndrome, with effects on glucose homeostasis, worsened by Se deficiency or a high-fat diet, and exacerbated in male mice. Our objective was to determine whether Se supplementation could ameliorate obesity and restore glucose homeostasis in the Scly KO mice.METHODSThree-weeks old male and female Scly KO mice were fed in separate experiments a diet containing 45 % kcal fat and either sodium selenite or a mixture of sodium selenite and selenomethionine (selenite/SeMet) at moderate (0.25 ppm) or high (0.5–1 ppm) levels for 9 weeks, and assessed for metabolic parameters, oxidative stress and expression of selenoproteins.RESULTSSe supplementation was unable to prevent obesity and elevated epididymal white adipose tissue weights in male Scly KO mice. Serum glutathione peroxidase activity in Scly KO mice was unchanged regardless of sex or dietary Se intake; however, supplementation with a mixture of selenite/SeMet improved oxidative stress biomarkers in the male Scly KO mice.CONCLUSIONThese results unveil sex- and selenocompound-specific regulation of energy metabolism after the loss of Scly, pointing to a role of this enzyme in the control of whole-body energy metabolism regardless of Se levels.     

Estrogens, inflammation and obesity: an overview

Emerging research has suggested that inflammatory stress may play a role in the development of obesity.Both the leptin and insulin receptor are sensitive to intracellular inflammatory signaling that ca...     

Pex11a deficiency causes dyslipidaemia and obesity in mice

Peroxisomes play a central role in lipid metabolism. We previously demonstrated that Pex11a deficiency impairs peroxisome abundance and fatty acid β‐oxidation and results in hepatic triglyceride accumulation. The role of Pex11a in dyslipidaemia and obesity is investigated here with Pex11a knockout mice (Pex11a^?/?). Metabolic phenotypes including tissue weight, glucose tolerance, insulin sensitivity, cholesterol levels, fatty acid profile, oxygen consumption, physical activity were assessed in wild‐type (WT) and Pex11a^?/? fed with a high‐fat diet. Molecular changes and peroxisome abundance in adipose tissue were evaluated through qRT‐PCR, Western blotting, and Immunofluorescence. Pex11a^?/? showed increased fat mass, decreased skeletal muscle, higher cholesterol levels, and more severely impaired glucose and insulin tolerance. Pex11a^?/? consumed less oxygen, indicating a decrease in fatty acid oxidation, which is consistent with the accumulation of very long‐ and long‐chain fatty acids. Adipose palmitic acid (C16:0) levels were elevated in Pex11a^?/?, which may be because of dramatically increased fatty acid synthase mRNA and protein levels. Furthermore, Pex11a deficiency increased ventricle size and macrophage infiltration, which are related to the reduced physical activity. These data demonstrate that Pex11a deficiency impairs physical activity and energy expenditure, decreases fatty acid β‐oxidation, increases de novo lipogenesis and results in dyslipidaemia and obesity.     

Sex difference in the relationship between the hypothalamic-pituitary-adrenal axis and sex hormones in obesity

Objective: This study was carried out to investigate the role of sex in the regulation of the hypothalamic‐pituitary‐adrenal (HPA) axis and its relationship with testosterone levels in male and female obesity. Research Methods and Procedures: Twenty‐two obese men (OB‐M) and 29 obese women (OB‐W) participated in the study. Two groups of normal weight men (NW‐M) and women (NW‐W), respectively, served as controls. In basal conditions, blood concentrations of major androgens, sex hormone—binding protein, and gonadotropins were assessed, and the free androgen index (testosterone ×100/ sex hormone‐binding globulin) was calculated. All subjects underwent a combined corticotropin‐releasing hormone plus arginine‐vasopressin stimulation test. Results: OB‐M and NW‐M had higher basal adrenal cortical tropic hormone (ACTH) and cortisol levels than their female counterparts. In addition, ACTH, but not cortisol basal, levels were significantly higher in obese than in normal weight controls in both sexes. OB‐W had a higher response than OB‐M to the combined corticotropin‐releasing hormone plus arginine‐vasopressin test of both ACTH and cortisol [expressed as incremental percentage of area under the curve (AUC%)]. The same finding was present between NW‐W and NW‐M. Basal luteinizing hormone levels were negatively correlated to ACTH_AUC% in both OB‐W and OB‐M. In the OB‐W, however, a positive correlation was found between cortisol_AUC% and testosterone (r = 0.48; p = 0.002), whereas a tendency toward a negative correlation was present in OB‐M. Discussion: In conclusion, we have shown a significant positive relationship between the activity of the HPA axis and testosterone in obese women, which suggests a partial responsibility of increased HPA axis activity in determining testosterone levels. In addition, it clearly seems that, as reported in normal weight subjects, a sex difference in the HPA axis activity still persists even in the presence of obesity.     

Sex differences in choline-deficient diet-induced steatohepatitis in mice

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are common liver diseases in the United States. ASH and NASH occur more frequently in women than in men, and liver injury is also more severe in women. The role of estrogens in ASH has been well established, but their role in NASH has received relatively little study. The purpose of this study was to evaluate the effect of estrogens in methionine-choline deficient diet (MCDD)-induced steatohepatitis in mice. The degree of steatohepatitis was evaluated in males and in intact and ovariectomized females that were fed MCDD for 4 weeks, and in females that were fed MCDD containing tamoxifen. Hematoxylin and eosin-stained sections of livers showed marked steatohepatitis in all experimental groups. Compared to the control group, markers of hepatocyte injury such as aspartate transaminase (AST), alanine transaminase (ALT), and liver triglyceride levels increased significantly in males and in intact and ovariectomized female mice that were fed MCDD. Also, it was interesting that levels of AST and ALT increased much more in the MCDD + tamoxifen group than in the MCDD group. In female mice fed MCDD, hepatocyte proliferative and apoptotic indices increased slightly compared to mice that were fed a normal diet. Based on these results, it can be concluded that MCDD-induced steatohepatitis is comparable in male and female mice, and that ovariectomy or antiestrogen treatment had no protective effect in MCDD-induced steatohepatitis.     

Cyclophilin D deficiency prevents diet-induced obesity in mice

Mitochondrial coupling efficiency is pivotal in thermogenesis and energy homeostasis. Here we show that deletion of cyclophilin D (CypD), a key modulator of the mitochondrial permeability transition pore, demonstrated resistance to diet-induced obesity (DIO) in both male and female mice, due to increased basal metabolic rate, heat production, total energy expenditure and expenditure of fat energy, despite increased food consumption. Absorption of fatty acids is not altered between CypD(-/-) and wild-type mice. Adult CypD(-/-) developed hyperglycemia, insulin resistance and glucose intolerance albeit resistant to DIO. These data demonstrate that inhibition of CypD function could protect from HFD-IO by increasing energy expenditure in both male and female mice. Inhibition of CypD may offer a novel target to modulate metabolism.     

Timing of food intake is more potent than habitual voluntary exercise to prevent diet-induced obesity in mice

Inappropriate eating habits such as skipping breakfast and eating late at night are associated with risk for abnormal weight-gain and adiposity. We previously reported that time-imposed feeding during the daytime (inactive phase) induces obesity and metabolic disorders accompanied by physical inactivity in mice. The present study compares metabolic changes induced in mice by time-imposed feeding under voluntary wheel-running (RW) and sedentary (SED) conditions to determine the effects of voluntary wheel-running activity on obesity induced in mice by feeding at inappropriate times. Mice were individually housed in cages with or without running-wheels. We compared food consumption, core body temperature, hormonal and metabolic variables in the blood, lipid accumulation in the liver, circadian expression of clock and metabolic genes in peripheral tissues, and gains in body weight between mice allowed access to food only during the sleep phase (daytime feeding; DF) or only during the active phase (nighttime feeding; NF) under SED or RW conditions. Only a high-fat high-sucrose diet was available to the mice throughout restricted feeding. Nocturnal activity was maintained in both NF and DF mice under RW conditions, but significantly suppressed during the latter half of the dark phase in DF mice. Nocturnal fluctuations in core body temperature were maintained in DF and NF mice under both SED and RW conditions, although DF attenuated the day–night amplitude more under SED, than RW conditions. The degrees of DF-induced increases in body weight gain, food efficiency, adipose tissue mass, lipogenic gene expression in metabolic tissues, and hepatic lipid accumulation were essentially identical between SED and RW conditions. Daytime feeding also induced hyperinsulinemia and hyperleptinemia under both SED and RW conditions, although DF-induced hyperleptinemia was slightly attenuated by wheel-running. The temporal expression of circadian clock genes became synchronized to feeding cycles in the liver but not in the skeletal muscle of mice under both SED and RW conditions. Chronic voluntary exercise on running-wheels minimally affected obesity and adiposity in mice caused by daily feeding at unusual times. The timing of food intake might be more important than physical exercise for preventing metabolic disorders.

Abbreviations: ANOVA: analysis of variance; DF: daytime feeding; FFA: free fatty acid; GLP-1: glucagon-like peptide-1; HOMA-IR: homeostasis model assessment of insulin resistance; NEAT: non-exercise activity thermogenesis; NF: nighttime feeding; RF: restricted feeding; RW: running-wheel; SCN: suprachiasmatic nucleus; SE: standard error of the mean; SED: sedentary; SPA: spontaneous physical activity; T-Cho: total cholesterol; TG: triglyceride; WAT: white adipose tissues     

Sex chromosome complement influences operant responding for a palatable food in mice

The procurement and consumption of palatable, calorie‐dense foods is influenced by the nutritional and hedonic value of foods. Although many factors can influence the control over behavior by foods rich in sugar and fat, emerging evidence indicates that biological sex may play a particularly crucial role in the types of foods individuals seek out, as well as the level of motivation individuals will exert to obtain those foods. However, a systematic investigation of food‐seeking and consumption that disentangles the effects of the major sex‐biasing factors, including sex chromosome complement and organizational and activational effects of sex hormones, has yet to be conducted. Using the four core genotypes mouse model system, we separated and quantified the effects of sex chromosome complement and gonadal sex on consumption of and motivation to obtain a highly palatable solution [sweetened condensed milk (SCM)]. Gonadectomized mice with an XY sex chromosome complement, compared with those with two X chromosomes, independent of gonadal sex, appeared to be more sensitive to the reward value of the SCM solution and were more motivated to expend effort to obtain it, as evidenced by their dramatically greater expended effort in an instrumental task with progressively larger response‐to‐reward ratios. Gonadal sex independently affected free consumption of the solution but not motivation to obtain it. These data indicate that gonadal and chromosomal sex effects independently influence reward‐related behaviors, contributing to sexually dimorphic patterns of behavior related to the pursuit and consumption of rewards.     

Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.     

Beneficial effect of oral administration of Lactobacillus casei strain Shirota on insulin resistance in diet-induced obesity mice

Aims: This study aimed at determining whether oral administration of a probiotic strain, Lactobacillus casei strain Shirota (LcS), can improve insulin resistance, which is the underlying cause of obesity‐associated metabolic abnormalities, in diet‐induced obesity (DIO) mice. Methods and Results: DIO mice were fed a high‐fat diet without or with 0·05% LcS for 4 weeks and then subjected to an insulin tolerance test (ITT) or oral glucose tolerance test (OGTT). Oral administration of LcS not only accelerated the reduction in plasma glucose levels during the ITT, but also reduced the elevation of plasma glucose levels during the OGTT. In addition, plasma levels of lipopolysaccharide‐binding protein (LBP), which is a marker of endotoxaemia, were augmented in the murine models of obese DIO, ob/ob, db/db and KK‐A^y and compared to those of lean mice. LcS treatment suppressed the elevation of plasma LBP levels in DIO mice, but did not affect intra‐abdominal fat weight. Conclusions: LcS improves insulin resistance and glucose intolerance in DIO mice. The reduction in endotoxaemia, but not intra‐abdominal fat, may contribute to the beneficial effects of LcS. Significance and Impact of the Study: This study suggests that LcS has the potential to prevent obesity‐associated metabolic abnormalities by improving insulin resistance.     

Neotomodon alstoni mice present sex differences between lean and obese in daily hypothalamic leptin signaling

This article compared the effects of spontaneous obesity on the daily profile in the relative amount of the leptin receptor (LepRb), and its output. That is the precursor Pro-opiomelanocortin (POMC) over a 24-hour period and compared with differences in locomotion and food intake in periods of artificial light. Differences between lean and obese mice were examined, as were sex differences. Body weight, food intake and locomotor activity were monitored in freely moving lean and obese mice. Hypothalamic tissue was collected at 5 h, 10 h, 15 h, 19 h and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein for LepRb, STAT3 phosphorylation (by pSTAT3/STAT3 ratio) and POMC. Obese mice were 60% less active in locomotion than lean mice during the night. While both locomotor activity and food intake were noticeably greater during the day in obese mice than in lean mice, the hypothalamus in obese mice showed a lower relative abundance of POMC and reduced pSTAT3/STAT3 ratio and leptin receptors. Behavioral and biochemical differences were more evident in obese females than in obese males. These results indicate that obesity in N. alstoni affects hypothalamic leptin signaling according to sex.     

视觉系统中的性别差异

大脑性别差异一直是神经科学领域中的一个热门话题.以前的性别差异研究往往关注与高级认知相关的脑区结构和功能差异,而对低级感知觉系统中的性别差异没有足够的重视.近年来,越来越多的研究结果表明,男性和女性在视知觉功能上也存在着明显的差异.本文首先回顾和梳理了视觉系统中存在性别差异的行为学和神经生物学证据,然后对视觉系统中性别...     

Trichinella spiralis infection ameliorated diet-induced obesity model in mice

Obesity is an increasingly prevalent disease worldwide, and genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases. Emerging studies indicate that innate and adaptive immune cell responses in adipose tissue play critical roles in the regulation of metabolic homeostasis. Parasitic helminths are the strongest natural inducers of type 2 inflammatory responses, and several studies have revealed that helminth infections inversely correlate with metabolic syndrome. Hence, this study investigated whether helminth infections could have preventative effects on high fat diet-induced obesity. Female C57BL/6 mice were maintained on either a low fat diet (LFD, 10% fat) or a high fat diet (HFD, 60% fat) for 6 weeks after Trichinella spiralis infection. The mice were randomly divided into four groups and were fed a normal diet, LFD, LFD after T. spiralis infection (Inf + LFD), a high fat diet (HFD), or HFD after T. spiralis infection (HFD + inf). All groups were assayed for body weight, food efficiency ratio (FER), total body weight gain (g)/total food intake amount (g) fat weight, and blood biochemical parameters. Our data indicate that the HFD + inf group significantly reduced body weight gain, fat mass, total cholesterol, and FER. Analysis of immune cell composition by flow cytometry revealed that T. spiralis promoted strong decreases in proinflammatory adipose macrophages (F4/80⁺CD11c⁺) and T cells. The alterations in microbiota from fecal samples of mice were analyzed, which showed that T. spiralis infection decreased the ratio of Firmicutes to Bacteriodetes, thereby restoring the previously increased ratio of Firmicutes to Bacteriodetes in HFD-fed mice. Moreover, elimination of T. spiralis retained the protective effects in the HFD-fed obese mice whereas flubendazole (FLBZ) treatment increased levels of the families Lachnospiraceae and Ruminococcaceae. In summary, we provided novel data suggesting that helminth infection protects against obesity and the protection was closely related to M2 macrophage proliferation, an inhibiting proinflammatory response. In addition, it alters the microbiota in the gut.