cortistatin-14 and Body-Weight

Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho) physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs) of SST- or CORT-knockout (KO) mice and their respective littermate-controls fed a low-fat (LF) or a high-fat (HF) diet for 16 wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF-I axis) involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology.

Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Female; Ghrelin; Growth Hormone; Insulin-Like Growth Factor I; Leptin; Mammary Glands, Animal; Mice; Mice, Knockout; Mice, Obese; Neuropeptides; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Somatostatin; Somatostatin; Up-Regulation

Adolescence is a period of transition from childhood to adulthood that involves the maturation of social and cognitive behavior. The activation of the stress system during this phase can lead to long-lasting adverse effects. We aimed to verify whether the nature and duration of stressors applied in adolescent female and male rats would alter their exploratory behavior and stress responses as adults. Wistar rats on day P26 were divided into groups that were subjected to 1 (acute) or 7 (chronic) insulin or lipopolysaccharide (LPS) injections or restraint stress for 1 h. At P60, the rats were subjected to the elevated plus-maze, and at P61, they were subjected to 30 min of restraint stress after which plasma samples and brains were collected. LPS acute injection promoted anxiolytic effects in male adults. Acute LPS treatment and acute or chronic restraint induced anxiolytic behavior in female adults. The administration of adolescent chronic stimuli to males decreased the adult plasma corticosterone (CORT) and progesterone levels after restraint. Adolescent acute restraint or LPS injection decreased the CORT response in female adults. The adult neuronal activation of the corticotrophin-releasing hormone and vasopressin on the paraventricular nucleus did not vary according to the type of adolescent stress or sex. Our results indicate that both adult behavior and the glucocorticoid stress response are affected differently in males versus females by adolescent stress. The duration of stressors had a greater effect on the CORT and progesterone response in males, whereas the nature of the stressor had a greater effect on exploratory behavior in females.

Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Corticosterone; Estradiol; Estrous Cycle; Exploratory Behavior; Female; Hypothalamo-Hypophyseal System; Insulin; Lipopolysaccharides; Male; Maze Learning; Neuropeptides; Pituitary-Adrenal System; Progesterone; Proto-Oncogene Proteins c-fos; Radioimmunoassay; Rats; Rats, Wistar; Restraint, Physical; Sex Characteristics; Stress, Psychological

The central melanocortin system regulates lipid metabolism in peripheral tissues such as white adipose tissue. Alterations in the activity of sympathetic nerves connecting hypothalamic cells expressing melanocortin 3/4 receptors (MC3/4R) with white adipocytes have been shown to partly mediate these effects. Interestingly, hypothalamic neurons producing corticotropin-releasing hormone and thyrotropin-releasing hormone co-express MC4R. Therefore we hypothesized that regulation of hypothalamo-pituitary adrenal (HPA) and hypothalamo-pituitary thyroid (HPT) axes activity by the central melanocortin system could contribute to its control of peripheral lipid metabolism. To test this hypothesis, we chronically infused rats intracerebroventricularly (i.c.v.) either with an MC3/4R antagonist (SHU9119), an MC3/4R agonist (MTII) or saline. Rats had been previously adrenalectomized (ADX) and supplemented daily with 1mg/kg corticosterone (s.c.), thyroidectomized (TDX) and supplemented daily with 10 μg/kgL-thyroxin (s.c.), or sham operated (SO). Blockade of MC3/4R signaling with SHU9119 increased food intake and body mass, irrespective of gland surgery. The increase in body mass was accompanied by higher epididymal white adipose tissue (eWAT) weight and higher mRNA content of lipogenic enzymes in eWAT. SHU9119 infusion increased triglyceride content in the liver of SO and TDX rats, but not in those of ADX rats. Concomitantly, mRNA expression of lipogenic enzymes in liver was increased in SO and TDX, but not in ADX rats. We conclude that the HPA and HPT axes do not play an essential role in mediating central melanocortinergic effects on white adipose tissue and liver lipid metabolism. However, while basal hepatic lipid metabolism does not depend on a functional HPA axis, the induction of hepatic lipogenesis due to central melanocortin system blockade does require a functional HPA axis.

Topics: Adipocytes, White; Adrenalectomy; Adrenocorticotropic Hormone; alpha-MSH; Animals; Body Weight; Corticosterone; Drug Delivery Systems; Eating; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Injections, Intraventricular; Liver; Male; Melanocortins; Melanocyte-Stimulating Hormones; Neuropeptides; Pituitary-Adrenal System; Rats; Rats, Wistar; Receptors, Corticotropin; Thyroidectomy; Thyroxine; Triglycerides

Chronic restraint stress, psychosocial stress, as well as systemic or oral administration of the stress-hormone corticosterone induces a morphological reorganization in the rat hippocampus, in which adrenal steroids and excitatory amino acids mediate a reversible remodeling of apical dendrites on CA3 pyramidal cell neurons of the hippocampus. This stress-induced neuronal remodeling is accompanied also by behavioral changes, some of which can be prevented with selective antidepressant and anticonvulsive drug treatments. Lithium is an effective treatment for mood disorders and has neuroprotective effects, which may contribute to its therapeutic properties. Thus, we wanted to determine whether lithium treatment could prevent the effects of chronic stress on CA3 pyramidal cell neuroarchitecture and the associated molecular and behavioral measures. Chronic lithium treatment prevented the stress-induced decrease in dendritic length, as well as the stress-induced increase in glial glutamate transporter 1 (GLT-1) mRNA expression and the phosphorylation of cAMP-response element binding in the hippocampus. Lithium treatment, however, did not prevent stress effects on behavior in the open field or the plus-maze. These data demonstrate that chronic treatment with lithium can protect the hippocampus from potentially deleterious effects of chronic stress on glutamatergic activation, which may be relevant to its therapeutic efficacy in the treatment of major depressive disorder and bipolar disorder.

Topics: Animals; Behavior, Animal; Body Weight; Excitatory Amino Acid Transporter 2; Hippocampus; Lithium; Male; Neurons; Neuropeptides; Rats; Stress, Physiological; Tranquilizing Agents