The effect of biofeedback pelvic floor training with ACTICORE1 on fecal incontinence A prospective multicentric cohort pilot study.

INTRODUCTION: Fecal incontinence refers to the inability to pass stool in a localized and timely manner resulting in the involuntary loss of intestinal contents such as air, intestinal mucus or stool. The prevalence of fecal incontinence in the general population is approximately 2-21%. Women are more frequently affected than men. Physiotherapeutically guided pelvic floor training, otherwise known as Kegel exercise, is the mainstay of treatment for fecal incontinence. The objective of this study was to evaluate the feasibility and potential benefits of a new biofeedback training, which uses a non-insertable pelvic floor sensor with digital interface, called ACTICORE1. METHODS: From January 2020 to April 2021, we conducted a prospective non-randomized multicentric clinical pilot study at the Alexianer St. Hedwig Hospital Berlin (Germany), private clinic Strack (Germany) and the University Hospital Magdeburg (Germany). Patients with fecal incontinence, defined as a Wexner score >2, were recruited and asked to either perform biofeedback training with ACTICORE1 (6 min daily for 16 weeks) or daily Kegel exercise (Physiotherapeutic guidance weekly for the first 6 weeks; biweekly for the remaining 10 weeks). The primary outcome was severity of fecal incontinence after 16 weeks of training assessed using the Wexner score. Secondary outcomes were severity of fecal incontinence after 12 weeks and patients' quality of life assessed using the EQ-5D-3L questionnaire after 16 weeks of training. The two-one-sided t-tests (TOST) procedure was used to determine if training with ACTICORE1 has equivalent or noninferior efficacies compared to Kegel exercise. RESULTS: A total of 40 individuals were included. Dropout occurred in 4 cases. The final sample included 19 patients who performed the ACTICORE1 training (ACTICORE-group) and 17 patients who performed guideline-based physiotherapy (PHYSIO-group). Univariate analysis of biometric parameters showed no statistically significant differences. Individuals in the ACTICORE-group were younger (M=46,6 (SD=18,9) years vs. M=57,1 (SD=17,3) years, p=0.093). In terms of endpoint evaluation, a non-inferiority of ACTICORE1 compared to the therapy standard (Kegel exercise) was detected. Both groups showed a statistically significant intraindividual improvement in fecal incontinence as measured by Wexner scoring after 16 weeks. The TOST detected a non-inferiority of ACTICORE1 training (98% confidence interval with equivalence bounds 5 for low and high; Results: 1.36, upper 6.75). CONCLUSION: Pelvic floor training with ACTICORE1 may enable sufficient pelvic floor training as a digital health application. The study at hand revealed a non-inferiority of ACTICORE1 training compared to Kegel exercise.

Nanowear on polymer films of different architecture.

In this paper, we describe atomic force microscope (AFM) friction experiments on different polymers. The aim was to analyze the influence of the physical architecture of the polymer on the degree and mode of wear and on the wear mode. Experiments were carried out with (1) linear polystyrene (PS) and cycloolefinic copolymers of ethylene and norbornene, which are stabilized by entanglements, (2) mechanically stretched PS, (3) polyisoprene-b-polystyrene diblock copolymers, with varying composition, (4) brush polymers consisting of a poly(methyl methacrylate) (PMMA) backbone and PS side chains, (5) PMMA and PS brushes grafted from a silicon wafer, (6) plasma-polymerized PS, and (7) chemically cross-linked polycarbonate. For linear polymers, wear depends critically on the orientation of the chains with respect to the scan direction. With increasing cross-link density, wear was reduced and ripple formation was suppressed. The cross-linking density was the dominating material parameter characterizing wear.

Chronic stress-induced effects of corticosterone on brain: direct and indirect.

Acutely, glucocorticoids act to inhibit stress-induced corticotrophin-releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) secretion through their actions in brain and anterior pituitary (canonical feedback). With chronic stress, glucocorticoid feedback inhibition of ACTH secretion changes markedly. Chronically stressed rats characteristically exhibit facilitated ACTH responses to acute, novel stressors. Moreover, in adrenalectomized rats in which corticosterone was replaced, steroid concentrations in the higher range are required for facilitation of ACTH responses to occur after chronic stress or diabetes. Infusion of corticosterone intracerebroventricularly into adrenalectomized rats increases basal ACTH, tends to increase CRF, and allows facilitation of ACTH responses to repeated restraint. Therefore, with chronic stressors, corticosterone seems to act in brain in an excitatory rather than an inhibitory fashion. We believe, under conditions of chronic stress, that there is an indirect glucocorticoid feedback that is mediated through the effects of the steroid +/- insulin on metabolism. Increased energy stores feedback on brain to inhibit hypothalamic CRF and decrease the expression of dopamine-beta-hydroxylase in the locus coeruleus. These changes would be expected to decrease the level of discomfort and anxiety induced by chronic stress. Moreover, central neural actions of glucocorticoids abet the peripheral effects of the steroids by increasing the salience and ingestion of pleasurable foods.

Individual mitochondrion characterization: a comparison of classical assays to capillary electrophoresis with laser-induced fluorescence detection.

A method has been developed that uses capillary electrophoresis (CE) with laser-induced fluorescence detection (LIF) for measuring protein abundance in individual mitochondria collected from a discontinuous density gradient and labeled with Mitotracker Green. From these measurements we determined the distribution of protein content per mitochondrion and the relative abundance of mitochondrial proteins in density gradient fractions. In addition, this method is useful for counting mitochondria and, as a consequence, determining the number of mitochondria per unit volume or estimate mitochondria copy number per cell. It was determined that mitochondria accumulate in two interfaces defined by consecutive layers of 35% Metrizamide, 17% Metrizamide, and 6% Percoll. The presence of mitochondria in these interfaces was also confirmed using a modified Lowry assay that prevents interference from Metrizamide and Percoll and determines total protein content, and a succinate dehydrogenase assay that uses dichloroindophenol as an electron acceptor and that specifically indicates abundance of mitochondria. The CE-LIF analysis of mitochondrial properties, based on the individual mitochondrial determinations, has a wider scope than the average values determined by enzymatic or bulk protein assays.

Regulation of microglia by CD4+ and CD8+ T cells: selective analysis in CD45-congenic normal and Toxoplasma gondii-infected bone marrow chimeras.

Microglia, the resident macrophage population of the central nervous system, is rapidly activated in murine Toxoplasma encephalitis (TE). However, the precise contribution of microglia to intracerebral immune reactions and the in vivo regulation of microglial activity are still poorly understood. To selectively analyse microglial reactions in TE, we have established a model of radiation-induced CD45-congenic bone marrow chimeras between CD45.2+ C57BL/6 (recipient) and CD45.1+ B6.SJL (donor) mice. These chimeras allow a differentiation of radioresistant CD45.2+ microglia from all other leukocytes, which exhibit the CD45.1+ haplotype. In the normal brain, microglia produced tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-10, and IL-15 mRNA. In TE, marked microglial activation was observed with a de novo expression of IL-12p40 and inducible nitric oxide synthase mRNA, upregulation of IL-1beta and TNF-alpha mRNA, a continuous production of IL-10, and IL-15 mRNA, an induction of major histocompatibility class I and II antigens, intercellular adhesion molecule-1, and leukocyte function-associated antigen-1. Furthermore, selective depletion of CD4+ and/or CD8+ T cells in the chimeras revealed that microglial cytokine production was critically regulated by CD8+T cells, whereas expression of cell surface molecules was less dependent on T cells. These findings demonstrate a specific regulation of microglia by T lymphocytes during the course of TE.

Bottomed out: metabolic significance of the circadian trough in glucocorticoid concentrations.

Mild chronic stressors characteristically increase circadian trough corticosteroid concentrations in rats and man. The elevation in trough concentrations is often accompanied by a reduction in peak concentrations and no change in the daily mean values. Here we point out that elevation of trough glucocorticoids, probably through daily increases of glucocorticoid receptor occupancy, has major metabolic effects that bias organisms toward storage of calories as fat. Thus, chronic mild stress, by overriding the normal mineralocorticoid receptor-mediated corticosteroid feedback regulation of trough CRF and ACTH secretion, facilitates development of the metabolic syndrome.

Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.

Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.

Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.

We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II (MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.

Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade.

Overexpression of agouti-related peptide (AgRP), an endogenous melanocortin (MC) 3 and 4 receptor antagonist (MC3/4-R), causes obesity. Exogenous AgRP-(83---132) increases food intake, but its duration and mode of action are unknown. We report herein that doses as low as 10 pmol can have a potent effect on food intake of rats over a 24-h period after intracerebroventricular injection. Additionally, a single third ventricular dose as low as 100 pmol in rats produces a robust increase in food intake that persists for an entire week. AgRP-(83---132) completely blocks the anorectic effect of MTII (MC3/4-R agonist), given simultaneously, consistent with a competitive antagonist action. However, when given 24 h prior to MTII, AgRP-(83---132) is ineffective at reversing the anorectic effects of the agonist. These results support a critical role of MC tone in limiting food intake and indicate that the orexigenic effects of AgRP-(83---132) are initially mediated by competitive antagonism at MC receptors but are sustained by alternate mechanisms.

Identification of receptors for neuromedin U and its role in feeding.

Neuromedin U (NMU) is a neuropeptide with potent activity on smooth muscle which was isolated first from porcine spinal cord and later from other species. It is widely distributed in the gut and central nervous system. Peripheral activities of NMU include stimulation of smooth muscle, increase of blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. An NMU receptor has not been molecularly identified. Here we show that the previously described orphan G-protein-coupled receptor FM-3 (ref. 15) and a newly discovered one (FM-4) are cognate receptors for NMU. FM-3, designated NMU1R, is abundantly expressed in peripheral tissues whereas FM-4, designated NMU2R, is expressed in specific regions of the brain. NMU is expressed in the ventromedial hypothalamus in the rat brain, and its level is significantly reduced following fasting. Intracerebroventricular administration of NMU markedly suppresses food intake in rats. These findings provide a molecular basis for the biochemical activities of NMU and may indicate that NMU is involved in the central control of feeding.

Starvation: early signals, sensors, and sequelae.

To identify the sequences of changes in putative signals, reception of these and responses to starvation, we sampled fed and starved rats at 2- to 6-h intervals after removal of food 2 h before dark. Metabolites, hormones, hypothalamic neuropeptide expression, fat depots, and leptin expression were measured. At 2 h, insulin decreased, and FFA and corticosterone (B) increased; by 4 h, leptin and glucose levels decreased. Neuropeptide Y messenger RNA (mRNA) increased 6 h after food removal and thereafter. Adrenal and plasma B did not follow ACTH and were elevated throughout, with a nadir at the dark-light transition. Leptin correlated inversely with adrenal B. Fat stores decreased during the last 12 h. Leptin mRNA in perirenal and sc fat peaked during the dark period, resembling plasma leptin in fed rats. We conclude that 1) within the first 4 h, hormonal and metabolic signals relay starvation-induced information to the hypothalamus; 2) hypothalamic neuropeptide synthesis responds rapidly to the altered metabolic signals; 3) catabolic activity quickly predominates, reinforced by elevated B, not driven by ACTH, but possibly to a minor extent by leptin, and more by adrenal neural activity; and 4) leptin secretion decreases before leptin mRNA or fat depot weight, showing synthesis-independent regulation.

Interactions among chronic cold, corticosterone and puberty on energy intake and deposition.

We have shown that chronic cold stress strongly interacts with corticosterone (B) to determine subsequent regulation of the hypothalamo-pituitary-adrenal (HPA) axis responses to novel stress. These studies, using the same 2 sets of rats, show that chronic cold also interacts with B and testosterone on signals of energy balance. The two groups of rats differed in weight by 20% and in age by 2 weeks (44-59 days of age). Adrenalectomized rats, replaced with varying doses of B, were exposed to cold or served as controls. Food intake and body weight during the experiments and hormones, metabolites and fat depots were measured on day 5. B, but not cold, affected food intake in the younger rats; by contrast, cold, but not B, affected food intake in the older rats. Testosterone was higher in older control rats and was markedly depressed by cold; younger rats had lower testosterone that was minimally affected by cold. Weight gain decreased in all rats at room temperature with increasing B, whereas they all lost weight in cold independently of B. Cold stimulated and B inhibited interscapular brown adipose tissue DNA content (reflecting sympathetic stimulation of thermogenesis). B stimulated insulin, whereas cold inhibited leptin and insulin; B also increased white adipose tissue weight gain in controls and inhibited its loss in cold. Leptin was unrelated to white adipose tissue depots in older control rats but was strongly related to these stores in younger rats and in all rats in cold. We conclude that: 1. By decreasing signals that act centrally to inhibit food intake (insulin, leptin and testosterone) cold allows B to stimulate food intake; 2. B inhibits weight gain although it causes accrual of fat; 3. Cold, probably through sympathetic stimulation of white adipose tissue, causes fat loss which is modulated by the inhibitory effect of B on sympathetic outflow; and, 4. The slope of the relationship between fat depot size and leptin becomes flatter in cold, possibly because of increased sympathetic outflow to these depots.

Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene.

Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes.

Central amygdala Fos expression during hypotensive or febrile, nonhypotensive endotoxemia in conscious rats.

The distribution and time course of Fos expression in neurons in the central nucleus of the amygdala (CeA) were studied in endotoxemic rats in two separate experiments. In each case, the severity of the endotoxin (lipopolysaccharide; LPS) challenge was characterized by using physiological outcome variables, including blood pressure and heart rate. Throughout the rostrocaudal extent of the CeA, extensive Fos staining was found 3 hours after injection with a hypotensive dose of Salmonella enteritidis LPS. Hypotension alone has been reported to induce Fos in the CeA; therefore, the remaining experiments were performed by using a lower dose of Escherichia coli LPS that did not cause hypotension. The nonhypotensive dose of E. coli LPS also induced Fos in large numbers of neurons of the CeA, with peak staining at 2 hours and Fos staining persisting for 6 hours after LPS injection. Tachycardia and fever after LPS also persisted for at least 6 hours. CeA Fos staining during nonhypotensive endotoxemia was predominantly located in the lateral subnucleus, although Fos-stained medial sub-nucleus neurons were also present. Additional forebrain regions that showed persistent Fos staining 6 hours after LPS included the parvocellular paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the medial preoptic area. Forebrain regions that contained Fos-stained nuclei at earlier time points, but not at 6 hours, included the supraoptic nucleus, magnocellular regions of the paraventricular nucleus of the hypothalamus, the subfornical organ, and the organum vasculosum of the lamina terminalis. Few CeA neurons showed Fos staining in rats that were restrained in a ventilated plastic tube. Neurons in the lateral septal nucleus and the medial amygdaloid nucleus, which have numerous Fos-stained nuclei after stressors such as footshock or restraint, did not show Fos staining above control levels after LPS administration. Activation of CeA neurons after intravenous LPS may indicate persistent drive from vagal afferents and may implicate the CeA in the autonomic, neuroendocrine, and/or behavioral responses to this treatment.

A hydrogen-sensing system in transcriptional regulation of hydrogenase gene expression in Alcaligenes species.

Heterologous complementation studies using Alcaligenes eutrophus H16 as a recipient identified a hydrogenase-specific regulatory DNA region on megaplasmid pHG21-a of the related species Alcaligenes hydrogenophilus. Nucleotide sequence analysis revealed four open reading frames on the subcloned DNA, designated hoxA, hoxB, hoxC, and hoxJ. The product of hoxA is homologous to a transcriptional activator of the family of two-component regulatory systems present in a number of H2-oxidizing bacteria. hoxB and hoxC predict polypeptides of 34.5 and 52.5 kDa, respectively, which resemble the small and the large subunits of [NiFe] hydrogenases and correlate with putative regulatory proteins of Bradyrhizobium japonicum (HupU and HupV) and Rhodobacter capsulatus (HupU). hoxJ encodes a protein with typical consensus motifs of histidine protein kinases. Introduction of the complete set of genes on a broad-host-range plasmid into A. eutrophus H16 caused severe repression of soluble and membrane-bound hydrogenase (SH and MBH, respectively) synthesis in the absence of H2. This repression was released by truncation of hoxJ. H2-dependent hydrogenase gene transcription is a typical feature of A. hydrogenophilus and differs from the energy and carbon source-responding, H2-independent mode of control characteristic of A. eutrophus H16. Disruption of the A. hydrogenophilus hoxJ gene by an in-frame deletion on megaplasmid pHG21-a led to conversion of the regulatory phenotype: SH and MBH of the mutant were expressed in the absence of H2 in response to the availability of the carbon and energy source. RNA dot blot analysis showed that HoxJ functions on the transcriptional level. These results suggest that the putative histidine protein kinase HoxJ is involved in sensing molecular hydrogen, possibly in conjunction with the hydrogenase-like polypeptides HoxB and HoxC.

A hypercaloric load induces thermogenesis but inhibits stress responses in the SNS and HPA system.

Caloric overingestion generates a sympathetic nervous system (SNS)-mediated increase in brown adipose tissue (BAT) thermogenesis; its effect on the hypothalamo-pituitary-adrenal (HPA) axis is unknown. To determine whether metabolic activation affects the HPA axis, male rats were provided palatable sucrose ad libitum. After 5 or 10 days of sucrose ingestion, BAT and basal and restraint-induced HPA variables were measured. Some rats were instrumented with temperature probes. BAT temperature and HPA axis responses to restraint were measured. Although caloric intake increased > or = 18%, body weight gain did not change after sucrose ingestion; DNA, protein, and uncoupling protein increased in BAT depots, and white adipose tissues were heavier after both 5 and 10 days. During days 5-10, the BAT-core temperature difference was +0.30 degrees C in sucrose rats and -0.46 degrees C in controls (P < 0.05); this, together with the biochemical changes, shows persistent activation of BAT by excess calories. Basal HPA measures were not altered. The sucrose group exhibited smaller BAT temperature and HPA responses to restraint on day 10; there was no HPA difference on day 5. We conclude that calorically mediated increases in BAT thermogenesis are independent of basal HPA activity; however, both systems respond concordantly to restraint stress. The diminished response to restraint in both systems in sucrose-fed rats may result from signals indicating increased energy stores.

Evidence that elevated plasma corticosterone levels are the cause of reduced hypothalamic corticotrophin-releasing hormone gene expression in diabetes.

Uncontrolled diabetes mellitus causes both a sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis and reduced expression of corticotrophin-releasing hormone (CRH) mRNA in the hypothalamic paraventricular nucleus (PVN). To investigate the role of glucocorticoids in the regulation of CRH mRNA expression in the PVN of diabetic rats, we studied surgically adrenalectomized (ADX) and sham-operated male Sprague-Dawley rats 4 days after i.v. injection of streptozotocin (STZ; 65 mg/kg i.v.) or vehicle. Among sham-operated animals, AM plasma corticosterone levels were significantly increased in diabetic as compared to nondiabetic animals (1.46+/-0.54 vs. 0.22+/-0.05 microg/dl; P <0.05), and were positively correlated to both plasma ACTH levels (r = 0.74; P = 0.015) and adrenal gland weight (r = 0.70; P = 0.025). In contrast, CRH mRNA levels measured in the PVN by in situ hybridization were inversely related to the plasma corticosterone level (r = -0.68; P = 0.045). In a second experiment, both diabetic and nondiabetic ADX rats received a continuous subcutaneous infusion of either corticosterone at one of two doses or its vehicle for 4 days. Among vehicle-treated ADX animals, STZ diabetes raised hypothalamic CRH mRNA levels, in contrast to the tendency for diabetes to lower CRH mRNA in intact rats in the first experiment. Corticosterone administration lowered CRH mRNA comparably in both diabetic and nondiabetic ADX rats. In contrast, diabetes reduced arginine vasopressin (AVP) mRNA levels in the PVN of ADX rats and blunted the inhibitory effect of glucocorticoids on AVP mRNA levels in this setting. We conclude (1) glucocorticoids are necessary for the effect of diabetes to reduce hypothalamic CRH gene expression, since diabetes causes a paradoxical increase in CRH mRNA levels in adrenalectomized animals; (2) glucocorticoid inhibition of hypothalamic CRH gene expression is intact in diabetic rats; and (3) the activation of the HPA axis by diabetes is associated with a proportionate decrease in PVN CRH gene expression. These findings support a model in which hypothalamic factors additional to CRH activate the HPA axis in uncontrolled diabetes, and inhibit CRH gene expression indirectly by negative glucocorticoid feedback.

Renal nerves do not modulate the renal and endocrine responses to furosemide in conscious lambs.

To test the hypothesis that renal sympathetic nerves influence the renal and renin responses to furosemide in conscious newborn animals, experiments were carried out in chronically instrumented lambs with either bilateral renal denervation (denervated, n = 7, age = 13 +/- 3 (SD) days) or intact renal sympathetic nerves (intact, n = 6, age = 13 +/- 4 (SD) days), at least 4 days after surgery. Basal glomerular filtration rate (GFR), urinary flow, and sodium excretion rates were similar in intact and denervated lambs (p > 0.5). A prompt diuretic and natriuretic response and a decrease in GFR occurred after i.v. furosemide (2 mg/kg); these responses were similar in intact and denervated lambs. Basal plasma renin activity (PRA) was not altered by renal denervation. PRA increased 10 min after furosemide (p < 0.001) and remained elevated at 90 min; the response was similar in both groups of lambs. Basal plasma aldosterone levels were elevated in denervated (191 +/- 232 (SD) pg/mL) compared with intact lambs (62 +/- 24 (SD) pg/mL). Plasma aldosterone levels increased after furosemide administration in both groups of animals. These data provide evidence to suggest that renal sympathetic nerves do not appear to modulate the renal and endocrine responses to furosemide, at least at a dose of 2 mg/kg. Our observations also support the premise that early in life, aldosterone counteracts the effects of renal denervation on fluid and electrolyte homeostasis.

Corticosterone regulation of insulin-like growth factor I, IGF-binding proteins, and growth in streptozotocin-induced diabetic rats.

The experiments reported herein were conducted to determine how corticosterone regulates growth and plasma insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP) concentrations in normal and streptozotocin (STZ)-induced diabetic rats. Males were bilaterally adrenalectomized (Ax) or sham Ax and given intravenous injections of 0, 30, or 65 mg STZ per kg body wt (0, 30, or 65 STZ) to induce varying degrees of insulin deficiency and implanted with 100-mg pellets containing 0, 40, or 80% corticosterone in cholesterol. Changes in plasma IGFBP concentrations were determined by Western ligand blotting or immunoblots. Neither IGFBP-5 nor IG-FBP-6 was detected in any of the treatment groups. Plasma IGFBP-2 was elevated and IGF-I was reduced in the nondiabetic Ax rats compared with sham Ax controls, but plasma IGFBP-3 and -4 were not significantly changed. Adrenalectomy had no affect on tibial growth or plasma IGFBP-1 in these animals. Plasma IGF-I, IGFBP-1 and -3, and tibial growth were equal among 0, 30, and 65 STZ Ax rats that did not receive corticosterone. Plasma IGFBP-4 was inversely related to the amount of STZ injected in these animals, and IGFBP-2 was elevated in those given the high dose of STZ. In the 0 STZ Ax rats, plasma IGF-I and IGFBP-3 increased in proportion to the corticosterone implant dose, but IGFBP-1 was unaffected. By contrast, IGF-I and IGFBP-3 were unaltered by corticosterone in the 30 STZ Ax rats, and IGFBP-1 increased in proportion with the dose of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

The neural network that regulates energy balance is responsive to glucocorticoids and insulin and also regulates HPA axis responsivity at a site proximal to CRF neurons.

The structure of a large neural system that responds to and regulates energy balance and that encompasses that PVN and activity of the HPA axis has begun to emerge from these experiments (Fig. 6). Several large loops have been delineated within this context of the maintenance of energy balance. Corticosteroids stimulate both feeding and insulin secretion. The actions of corticosteroids in the periphery are catabolic, causing mobilization of energy stores; their actions in the central nervous system are stimulatory to energy acquisition (food intake). By contrast, the action of insulin in the periphery is anabolic, causing energy storage; its action in the central nervous system is inhibitory to energy acquisition (food intake). At the level of the CNS, insulin inhibits and corticosteroids stimulate expression of NPY mRNA in the arcuate nuclei, and these actions may explain, in part, the reciprocal actions of the hormones on energy acquisition. Thus over the long term, stimulation of insulin secretion by corticosteroids tends to supply an automatic brake on the effects of corticosteroids on feeding. The neural system that controls energy balance and responds to the reciprocal signals of corticosterone and insulin also regulates responsivity to restraint stress in the HPA axis. The low-amplitude ACTH responses to restraint, corticosteroid feedback, and prior stress-induced facilitation that are observed under conditions of relative fasting in the PM can be produced in the AM by a 14-h, overnight fast. By contrast, NPY injected ivt stimulates identical ACTH responses in the AM in fed rats and in rats fasted overnight, suggesting that NPY acts to stimulate CRF secretion at a site closer to the PVN than the stress of restraint, which is filtered through the neural energy balance system. In the periphery, corticosteroids and insulin also have reciprocal effects on energy storage; effects that are opposite those exerted in the CNS on energy acquisition. Thus, together, the two hormones may be construed as a bihormonal system that regulates overall energy balance. Although under normal conditions this system is well designed to accomplish energy balance, and provides a mechanism by which total energy stores may be increased appropriately (e.g., prior to hibernation or migration), it seems probable that under conditions of chronic stress, this regulatory system may be maladaptive. Chronic stress and glucocorticoid treatment cause increases in mean daily concentrations of both corticosteroids and insulin. Increases in the absolute levels of both hormones, with the normal ratio between them maintained, results in remodeling of body energy stores-away from muscle stores and toward fat stores, particularly abdominal fat stores. It seems quite likely that some conditions of abdominal obesity in man may be explained, at least in part, by increased activity in the HPA axis. Because abdominal obesity is associated with cardiovascular diseases, these responses, when they persist, are clearly maladaptive. Exploration of the role and control of the HPA axis in and by the larger neural network that regulates energy balance has to date been instructive. Clearly this work has just begun and is primarily still at the level of phenomenology. However, once the phenomenology is understood, mechanistic work can be performed that will flesh out our understanding of this very large and physiologically essential system.