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The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
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Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK
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Adverse environmental conditions before birth are known to programme adult metabolic and endocrine phenotypes in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose–insulin dynamics and pituitary–adrenal function in adult sheep. Compared with saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb body weight at 1–2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic–euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline-treated group. The results show that cortisol overexposure before birth programmes pituitary–adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.
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Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
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Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
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Short-chain fatty acids (SCFAs) are key nutrients that play a diverse set of roles in physiological function, including regulating metabolic homeostasis. Generated through the fermentation of dietary fibers in the distal colon by the gut microbiome, SCFAs and their effects are partially mediated by their cognate receptors, including free fatty acid receptor 2 (FFA2). FFA2 is highly expressed in the intestinal epithelial cells, where its putative functions are controversial, with numerous in vivo studies relying on global knockout mouse models to characterize intestine-specific roles of the receptor. Here, we used the Villin-Cre mouse line to generate a novel, intestine-specific knockout mouse model for FFA2 (Vil-FFA2) to investigate receptor function within the intestine. Because dietary changes are known to affect the composition of the gut microbiome, and can thereby alter SCFA production, we performed an obesogenic challenge on male Vil-FFA2 mice and their littermate controls (FFA2-floxed, FFA2fl/fl) to identify physiological changes on a high-fat, high-sugar ‘Western diet’ (WD) compared to a low-fat control diet (CD). We found that the WD-fed Vil-FFA2 mice were transiently protected from the obesogenic effects of the WD and had lower fat mass and improved glucose homeostasis compared to the WD-fed FFA2fl/fl control group during the first half of the study. Additionally, major differences in respiratory exchange ratio and energy expenditure were observed in the WD-fed Vil-FFA2 mice, and food intake was found to be significantly reduced at multiple points in the study. Taken together, this study uncovers a novel role of intestinal FFA2 in mediating the development of obesity.
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During pregnancy the maternal pancreatic islets of Langerhans undergo adaptive changes to compensate for gestational insulin resistance. The lactogenic hormones are well established to play a key role in regulating the islet adaptation to pregnancy, and one of the mechanisms through which they act is through upregulating β-cell serotonin production. During pregnancy islet serotonin levels are significantly elevated, where it is released from the β-cells to drive the adaptive response through paracrine and autocrine effects. We have previously shown that placental kisspeptin (KP) also plays a role in promoting the elevated insulin secretion and β-cell proliferation observed during pregnancy, although the precise mechanisms involved are unclear. In the present study we investigated the effects of KP on expression of pro-proliferative genes and serotonin biosynthesis within rodent islets. Whilst KP had limited effect on pro-proliferative gene expression at the time points tested, KP did significantly stimulate expression of the serotonin biosynthesis enzyme Tph-1. Furthermore, the islets of pregnant β-cell-specific GPR54 knockdown mice were found to contain significantly fewer serotonin-positive β-cells when compared to pregnant controls. Our previous studies suggested that reduced placental kisspeptin production, with consequent impaired kisspeptin-dependent β-cell compensation, may be a factor in the development of GDM in humans. These current data suggest that, similar to the lactogenic hormones, KP may also contribute to serotonin biosynthesis and subsequent islet signalling during pregnancy. Furthermore, upregulation of serotonin biosynthesis may represent a common mechanism through which multiple signals might influence the islet adaptation to pregnancy.
Neuroscience Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Hebei Medical University, Shijiazhuang, Hebei, China
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Neuroscience Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Hebei Medical University, Shijiazhuang, Hebei, China
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Neuroscience Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Hebei Medical University, Shijiazhuang, Hebei, China
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Neuroscience Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Hebei Medical University, Shijiazhuang, Hebei, China
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Neuroscience Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Hebei Medical University, Shijiazhuang, Hebei, China
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Neuroscience Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Hebei Medical University, Shijiazhuang, Hebei, China
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Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2–CREB signaling pathway in an AR-independent manner.
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Department of Child Health, University of Arizona College of Medicine, Phoenix, Arizona, USA
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Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
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Traumatic brain injury (TBI) can damage the hypothalamus and cause improper activation of the growth hormone (GH) axis, leading to growth hormone deficiency (GHD). GHD is one of the most prevalent endocrinopathies following TBI in adults; however, the extent to which GHD affects juveniles remains understudied. We used postnatal day 17 rats (n = 83), which model the late infantile/toddler period, and assessed body weights, GH levels, and number of hypothalamic somatostatin neurons at acute (1, 7 days post injury (DPI)) and chronic (18, 25, 43 DPI) time points. We hypothesized that diffuse TBI would alter circulating GH levels because of damage to the hypothalamus, specifically somatostatin neurons. Data were analyzed with generalized linear and mixed effects models with fixed effects interactions between the injury and time. Despite similar growth rates over time with age, TBI rats weighed less than shams at 18 DPI (postnatal day 35; P = 0.03, standardized effect size [d] = 1.24), which is around the onset of puberty. Compared to shams, GH levels were lower in the TBI group during the acute period (P = 0.196; d = 12.3) but higher in the TBI group during the chronic period (P = 0.10; d = 52.1). Although not statistically significant, TBI-induced differences in GH had large standardized effect sizes, indicating biological significance. The mean number of hypothalamic somatostatin neurons (an inhibitor of GH) positively predicted GH levels in the hypothalamus but did not predict GH levels in the somatosensory cortex. Understanding TBI-induced alterations in the GH axis may identify therapeutic targets to improve the quality of life of pediatric survivors of TBI.
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The Lawson Health Research Institute and the Children's Health Research Institute, London, Ontario, Canada
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Reports in North America suggest that up to 20% of young women (18–24 years) use cannabis during pregnancy. This is concerning given clinical studies indicate that maternal cannabis use is associated with fetal growth restriction and dysglycemia in the offspring. Preclinical studies demonstrated that prenatal exposure to Δ9-tetrahydrocannabinol, the main psychoactive component of cannabis, in rat dams led to female-specific deficits in β-cell mass and glucose intolerance/insulin resistance. Yet to date, the contributions of cannabidiol (CBD), the primary nonpsychoactive compound in cannabis, remain elusive. This study aimed to define the effects of in utero cannabidiol (CBD) exposure on postnatal glucose regulation. Pregnant Wistar rat dams received daily intraperitoneal injections of either a vehicle solution or 3 mg/kg of CBD from gestational day (GD) 6 to parturition. CBD exposure did not lead to observable changes in maternal or neonatal outcomes; however, by 3 months of age male CBD-exposed offspring exhibited glucose intolerance despite no changes in pancreatic β/α-cell mass. Transcriptomic analysis on the livers of these CBD-exposed males revealed altered gene expression of circadian rhythm clock machinery, which is linked to systemic glucose intolerance. Furthermore, alterations in hepatic developmental and metabolic processes were also observed, suggesting gestational CBD exposure has a long-lasting detrimental effect on liver health throughout life. Collectively, these results indicate that exposure to CBD alone in pregnancy may be detrimental to the metabolic health of the offspring later in life.
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The prevalence of obesity is increasing exponentially across the globe. The lack of effective treatment options for long-term weight loss has magnified the enormity of this problem. Studies continue to demonstrate that adipose tissue holds a biological memory, one of the most important determinant of long-term weight maintenance. This phenomenon is consistent with the metabolically dynamic role of adipose tissue: it adapts and expands to store for excess energy and serves as an endocrine organ capable of synthesizing a number of biologically active molecules that regulate metabolic homeostasis. An important component of the plasticity of adipose tissue is the extracellular matrix, essential for structural support, mechanical stability, cell signaling and function. Chronic obesity upends a delicate balance of extracellular matrix synthesis and degradation, and the ECM accumulates in such a way that prevents the plasticity and function of the diverse cell types in adipose tissue. A series of maladaptive responses among the cells in adipose tissue leads to inflammation and fibrosis, major mechanisms that explain the link between obesity and insulin resistance, risk of type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Adipose tissue fibrosis persists after weight loss and further enhances adipose tissue dysfunction if weight is regained. Here, we highlight the current knowledge of the cellular events governing adipose tissue ECM remodeling during the development of obesity. Our goal is to delineate the relationship more clearly between adipose tissue ECM and metabolic disease, an important step toward better defining the pathophysiology of dysfunctional adipose tissue.
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The metabolic health trajectory of an individual is shaped as early as prepregnancy, during pregnancy, and lactation period. Both maternal nutrition and metabolic health status are critical factors in the programming of offspring toward an increased propensity to developing type 2 diabetes in adulthood. Pancreatic beta-cells, part of the endocrine islets, which are nutrient-sensitive tissues important for glucose metabolism, are primed early in life (the first 1000 days in humans) with limited plasticity later in life. This suggests the high importance of the developmental window of programming in utero and early in life. This review will focus on how changes to the maternal milieu increase offspring’s susceptibility to diabetes through changes in pancreatic beta-cell mass and function and discuss potential mechanisms by which placental-driven nutrient availability, hormones, exosomes, and immune alterations that may impact beta-cell development in utero, thereby affecting susceptibility to type 2 diabetes in adulthood.
