Kurt E. Borg

Assessment of the Primary Adrenal Cortical and Pancreatic Hormone Basal Levels in Relation to Plasma Glucose and Age in the Unstressed Ames Dwarf Mouse

Abstract Peripheral glucose concentrations in mammals are maintained within very narrow limits to provide a continuous, uninterrupted supply of this nutrient to tissues. Numerous factors have been shown to influence and/or regulate glucose levels. One such influence is growth hormone (GH) produced by the pituitary somatotrophs. Several animal models of hyposomatotropism are available in which GH secretion or actions are suppressed due to genetic abnormalities. One such model, the Ames dwarf mouse (df/df), has arisen from an autosomal recessive mutation in which GH-, prolactin- (PRL), and thyroid-stimulating hormone (TSH)-producing cell types of the anterior pituitary fail to develop. The current investigation examined the effects of GH deficiency on glucose, insulin, and corticosterone levels using male and female df/df mice and their normal (Df/-) littermates. Additionally, old and young females of both genotypes were used to determine whether aging and GH deficiency interact to influence insulin, corticosterone or glucose levels in these animals. Plasma samples collected from unstressed animals (normal, df/df; young [5 months], old [17-19 months]; male, female) were used. Glucose levels were lower (P < 0.05) in df/df than in Df/-mice regardless of sex and age. A sex difference in Df/- animals was evident—young and old females had significantly lower levels of glucose when compared with young Df/- males. Plasma insulin was elevated (P < 0.05) in old df/df females compared with young df/df and Df/- females. Young Df/- males had the highest insulin levels compared with all genotype and age groups. This observation paralleled results from glucose measurements. Corticosterone levels were highest in young Df/-females and lowest in young Df/- males, with df/df animals falling between these values. Plasma corticosterone levels in old Df/- females did not differ from the values measured in dwarfs. The present findings indicate that glucose and factors affecting glucose levels are altered in the df/df mouse. These results provide new insights into the roles GH may play in glucose metabolism and perhaps also in adiposity which is a common characteristic of Df/- aged females from this line of mice.

PROLACTIN REGULATION OF PIM-1 EXPRESSION : POSITIVE AND NEGATIVE PROMOTER ELEMENTS

The lactogen-dependent rat Nb2 lymphoma is a useful model to investigate PRL signaling pathways that lead to regulation of gene transcription. A primary mechanism coupled to PRL receptor (PRLR) activation in Nb2 cells involves phosphorylation by Jak-family tyrosine kinases of one or more signal transducers and activators of transcription (Stat) factors which subsequently bind to γ-interferon activation sequences (GAS) within promoter regions of target genes. However, it is presently unclear whether this mechanism is operative as a means for regulating PRL-induced gene expression to the exclusion of other signaling pathways. Previously, we reported that PRL directly stimulated rapid expression of the protooncogene, pim-1, at the mRNA and protein levels in lactogen-dependent Nb2–11 cells. In the present study, experiments were conducted to evaluate signaling mechanisms by which PRL regulates transcription of pim-1. Toward this end, a 1,268-bp segment upstream of the transcription initiation site of the 5′-p...

Functioning of the porcine pituitary-adrenocortical axis during neonatal development

A study was conducted with neonatal boars to measure age-related changes in functioning of the pituitary-adrenocortical axis. Pigs were randomly assigned to control (n = 7-10/age) or treated (1-min restraint, n = 9-11/age) groups to be sampled at either 12, 19, or 26 days of age. Blood samples were taken via catheter 10 min before and 3, 10, and 20 min after restraint or at similar time intervals in controls. One day later, pigs were killed and adrenal glands obtained for ACTH receptor measurements. Basal plasma ACTH concentrations were greatest (p = 0.035) on day 12 when compared with later ages, but basal plasma cortisol concentrations were comparable at the three ages. Compared with controls, restraint elevated incremental plasma ACTH and cortisol responses at each age (p < 0.004). On day 12, maximal plasma ACTH (p = 0.0006) and incremental cortisol (p < 0.006) responses to restraint were greater than at later ages. Binding to adrenal ACTH receptors was greatest (p < 0.05) at day 13, which may help explain the apparently increased in vivo response of the adrenal gland to ACTH at this time. Restrained pigs had increased growth rates with increasing age (p = 0.016) whereas growth rates for control pigs did not differ with age. At day 27, 24 h after the 1-min restraint, body weights of restrained pigs exceeded those of control pigs (p = 0.045). At day 20, adrenal DNA and protein in pigs restrained 24 h previously were greater than in control pigs (p < 0.05). These data suggest age-related changes in functioning of the pituitary-adrenal axis in neonatal boars, and an absence of period during neonatal life when the porcine pituitary adrenocortical axis cannot respond to a stressor. The data also indicate both rapid and long-term responses of the adrenal to a very modest stressor and suggest an extreme sensitivity of neonatal pigs to environmental perturbations.

Growth Hormone and Aging in Mice

After decades of research, the physiological mechanisms leading to aging are still poorly understood. A number of studies have shown that the endocrine system is intimately involved in the control of aging processes. The somatotropic axis, in particular, has come to the forefront as a major player in aging and longevity. Many of these reports derive data from multiple endocrine mutants, those that exhibit elevated levels of both growth hormone (GH) and insulin-like growth factor I (IGF-I) or deficiencies in one or both of these hormones. In general, both spontaneous and genetically engineered GH and IGF-I deficiencies have led to small body size, delayed development of both sexual maturation and age-related pathologic conditions, and life-span extension. In contrast, high levels of circulating GH have led to larger body sizes, early puberty and reproductive senescence, increased cancer incidence, and reduced life span compared with wild-type animals with normal plasma hormone concentrations. This information, along with that found in multiple other species, implicates this anabolic pathway as the major regulator of longevity in animals.

Metabolic adaptation of short‐living growth hormone transgenic mice to methionine restriction and supplementation

Extension of mammalian health and life span has been achieved using various dietary interventions. We previously reported that restricting dietary methionine (MET) content extends life span only when growth hormone signaling is intact (no life span increase in GH deficiency or GH resistance). To understand the metabolic responses of altered dietary MET in the context of accelerated aging (high GH), the current study evaluated MET and related pathways in short‐living GH transgenic (GH Tg) and wild‐type mice following 8 weeks of restricted (0.16%), low (0.43%), or enriched (1.3%) MET consumption. Liver MET metabolic enzymes were suppressed in GH Tg compared to diet‐matched wild‐type mice. MET metabolite levels were differentially affected by GH status and diet. SAM:SAH ratios were markedly higher in GH Tg mice. Glutathione levels were lower in both genotypes consuming 0.16% MET but reduced in GH Tg mice when compared to wild type. Tissue thioredoxin and glutaredoxin were impacted by diet and GH status. The responsiveness to the different MET diets is reflected across many metabolic pathways indicating the importance of GH signaling in the ability to discriminate dietary amino acid levels and alter metabolism and life span.

A summary of the Proceedings of the Tenth International Symposium on the Neurobiology and Neuroendocrinology of Aging Bregenz, Austria, July 25-30, 2010

A summary of the Eleventh International Symposium on the Neurobiology and Neuroendocrinology of Aging that was held in July 29-August 3 in Bregenz, Austria, is presented. Sixteen of the speakers who presented at the conference submitted review papers covering the topic of their presentation as well as an overview of their respective fields and are included in this special issue. The abstracts from each poster presentation are also included at the end of the special issue.