scholarly journals The Pituitary Gland is a Novel Major Site of Action of Metformin in Non-Human Primates: a Potential Path to Expand and Integrate Its Metabolic Actions

2018 ◽  
Vol 49 (4) ◽  
pp. 1444-1459 ◽  
Author(s):  
Mari C. Vázquez-Borrego ◽  
Antonio C. Fuentes-Fayos ◽  
Manuel D. Gahete ◽  
Justo P. Castaño ◽  
Rhonda D. Kineman ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Signaling Pathways ◽  
Pituitary Hormones ◽  
Pituitary Cell ◽  
Metabolic Effects ◽  
Primate Species ◽  
Whole Body ◽  
Endocrine Gland ◽  
Papio Anubis ◽  
Human Primate

Background/Aims: Biguanides are anti-hyperglycaemic agents used to treat diabetes by acting primarily on the liver, inhibiting hepatic gluconeogenesis. However, biguanides may target other key metabolic tissues to exert beneficial actions. As the “master endocrine gland”, the pituitary is a true homeostatic sensor that controls whole body homeostasis and metabolism by integrating central and peripheral signals. However, whether the pituitary is a primary site of biguanides action in normal adult humans/primates remains unknown. Therefore, we aimed to elucidate the direct effects of two biguanides (metformin/phenformin) on the expression and secretion of all anterior pituitary hormones in two non-human primate species (Papio anubis and Macaca fascicularis), and the molecular/signalling-mechanisms behind these actions. Methods: Primary pituitary cell cultures from baboons and macaques were used to determine the direct impact of metformin/phenformin (alone and combined with primary regulators) on the functioning of all pituitary cell-types (i.e. expression/secretion/signaling-pathways, etc). Results: Metformin/phenformin inhibited basal, but not GHRH/ghrelin-stimulated GH/ACTH/ FSH-secretion and GH/POMC-expression, without altering secretion or expression of other pituitary hormones (PRL/LH/TSH), FSH-expression or cell viability in both primate models. These biguanide actions are likely mediated through modulation of: 1) common (mTOR/PI3K/intracellular-Ca2+mobilization) and distinct (MAPK) signaling pathways; and 2) gene expression of key receptors regulating somatotrope/corticotrope/gonadotrope function (i.e. upregulation of SSTR2/SSTR5/INSR/IGF1R/LEPR). Conclusion: The pituitary gland is a primary target of biguanide actions wherein they modulate somatotrope/corticotrope/gonadotrope-function through multiple molecular/signaling pathways in non-human primate-models. This suggests that the well-known metabolic effects of biguanides might be, at least in part, influenced by their actions at the pituitary level.

scholarly journals Melatonin Regulates Somatotrope and Lactotrope Function Through Common and Distinct Signaling Pathways in Cultured Primary Pituitary Cells From Female Primates

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 1100-1110 ◽  
Author(s):  
Alejandro Ibáñez-Costa ◽  
José Córdoba-Chacón ◽  
Manuel D. Gahete ◽  
Rhonda D. Kineman ◽  
Justo P. Castaño ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Signaling Pathways ◽  
Somatostatin Receptors ◽  
Cell Types ◽  
Pituitary Hormones ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Primate Model ◽  
Direct Role ◽  
Precise Relationship

Abstract Melatonin (MT) is secreted by the pineal gland and exhibits a striking circadian rhythm in its release. Depending on the species studied, some pituitary hormones also display marked circadian/seasonal patterns and rhythms of secretion. However, the precise relationship between MT and pituitary function remains controversial, and studies focusing on the direct role of MT in normal pituitary cells are limited to nonprimate species. Here, adult normal primate (baboons) primary pituitary cell cultures were used to determine the direct impact of MT on the functioning of all pituitary cell types from the pars distalis. MT increased GH and prolactin (PRL) expression/release in a dose- and time-dependent fashion, a response that was blocked by somatostatin. However, MT did not significantly affect ACTH, FSH, LH, or TSH expression/release. MT did not alter GHRH- or ghrelin-induced GH and/or PRL secretions, suggesting that MT may activate similar signaling pathways as ghrelin/GHRH. The effects of MT on GH/PRL release, which are likely mediated through MT1 receptor, involve both common (adenylyl cyclase/protein kinase A/extracellular calcium-channels) and distinct (phospholipase C/intracellular calcium-channels) signaling pathways. Actions of MT on pituitary cells also included regulation of the expression of other key components for the control of somatotrope/lactotrope function (GHRH, ghrelin, and somatostatin receptors). These results show, for the first time in a primate model, that MT directly regulates somatotrope/lactotrope function, thereby lending support to the notion that the actions of MT on these cells might substantially contribute to the define daily patterns of GH and PRL observed in primates and perhaps in humans.

scholarly journals Kisspeptin Regulates Gonadotroph and Somatotroph Function in Nonhuman Primate Pituitary via Common and Distinct Signaling Mechanisms

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 957-966 ◽  
Author(s):  
Raúl M. Luque ◽  
José Córdoba-Chacón ◽  
Manuel D. Gahete ◽  
Víctor M. Navarro ◽  
Manuel Tena-Sempere ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Mammalian Target Of Rapamycin ◽  
Pituitary Hormones ◽  
Pituitary Cell ◽  
Papio Anubis ◽  
Primate Model ◽  
Reproductive Axis ◽  
Gnrh Release ◽  
Oxide Synthase

Kisspeptins (Kps) have emerged as key players in the control of reproductive-axis function, in which they operate as primary regulators of hypothalamic GnRH release. In addition, recent data indicate that Kps can also directly act on the pituitary to stimulate LH and GH release in primary pituitary cell culture prepared from rats, cows, and sheep. We present herein evidence that Kps (specifically Kp-10) can also stimulate LH and GH release in primary pituitary cell cultures prepared from female baboons (Papio anubis), a species that more closely models human physiology. The stimulatory effect of Kp-10 on LH and GH release was dose and time dependent and enhanced the hormonal responses to their major regulators (GnRH for LH; GHRH/ghrelin for GH) without affecting the release of other pituitary hormones (TSH, FSH, ACTH, prolactin). Use of pharmacological intracellular signaling blockers indicated Kp-10 signals through phospholipase C, protein kinase C, MAPK, and intracellular Ca2+ mobilization, but not adenylyl cyclase, protein kinase A, extracellular Ca2+ influx (through L-type channels), or nitric oxide synthase, to stimulate both LH and GH release. Interestingly, blockade of mammalian target of rapamycin or phosphoinositol 3-kinase activity fully abolished the stimulatory effect of Kp-10 on LH but not GH release. Of note, estradiol enhanced the relative LH response to Kp-10, alone or in combination with GnRH. In sum, our data are the first to provide evidence that, in a primate model, there is a functional Kp-signaling system within the pituitary, which is dynamically regulated and may contribute to the direct control of gonadotropic and somatotropic axes.

Primary Amenorrhoea with Pituitary Dwarfism: A rare case report

2016 ◽  
Vol 2 (2) ◽  
pp. 145-147
Author(s):  
Siva S ◽  
Divya Gopineni ◽  
Shafi P ◽  
Chandra Sekhar
Keyword(s):  
Pituitary Gland ◽  
General Medicine ◽  
Pituitary Hormones ◽  
Thyroid Stimulating Hormone ◽  
Primary Amenorrhea ◽  
Pituitary Dwarfism ◽  
Primary Amenorrhoea ◽  
Sexual Characteristics ◽  
Loss Of Appetite ◽  
Secondary Sexual

Females with pituitary dwarfism and a multiple deficiency of pituitary hormones show ovarian dysfunction due to hypogonadotropism. Primary amenorrhea can be diagnosed if a patient has normal secondary sexual characteristics but no menarche by 16 years of age. A 16 year-old female patient admitted in general medicine department with chief complaints of shortness of breath on exertion since 15 days, swelling of both legs since 10 days, loss of weight since 5 months, loss of appetite since 3 months, history of pain during swallowing. Pelvis scan examination reveals that uterus measures 3.2×0.5×0.5cm; uterus is hypo plastic, ovaries not visualized. Patient parents reveled that from patient birth to 11years of age her growth and other developments were normal, after that her growth is stopped and no changes were observed in development since 5 years. Patient has hypothyroidism so pituitary gland make an important role to maintain hormone levels, pituitary gland produces thyroid stimulating hormone (TSH) which stimulates thyroid gland to produce thyroid hormones. Primary Amenorrhea, short stature and poorly developed secondary sexual characters which could have been contributed and should be subjected for karyotyping. This type of Pituitary Dwarfism is very difficult to manage.

scholarly journals Using a simple rope-pulley system that mechanically couples the arms, legs, and treadmill reduces the metabolic cost of walking

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Daisey Vega ◽  
Christopher J. Arellano
Keyword(s):  
Metabolic Cost ◽  
Metabolic Energy ◽  
Metabolic Effects ◽  
Whole Body ◽  
Walking Ability ◽  
Arm Swing ◽  
Pulley System ◽  
Young Subjects ◽  
Walking Recovery ◽  
Set Up

Abstract Background Emphasizing the active use of the arms and coordinating them with the stepping motion of the legs may promote walking recovery in patients with impaired lower limb function. Yet, most approaches use seated devices to allow coupled arm and leg movements. To provide an option during treadmill walking, we designed a rope-pulley system that physically links the arms and legs. This arm-leg pulley system was grounded to the floor and made of commercially available slotted square tubing, solid strut channels, and low-friction pulleys that allowed us to use a rope to connect the subject’s wrist to the ipsilateral foot. This set-up was based on our idea that during walking the arm could generate an assistive force during arm swing retraction and, therefore, aid in leg swing. Methods To test this idea, we compared the mechanical, muscular, and metabolic effects between normal walking and walking with the arm-leg pulley system. We measured rope and ground reaction forces, electromyographic signals of key arm and leg muscles, and rates of metabolic energy consumption while healthy, young subjects walked at 1.25 m/s on a dual-belt instrumented treadmill (n = 8). Results With our arm-leg pulley system, we found that an assistive force could be generated, reaching peak values of 7% body weight on average. Contrary to our expectation, the force mainly coincided with the propulsive phase of walking and not leg swing. Our findings suggest that subjects actively used their arms to harness the energy from the moving treadmill belt, which helped to propel the whole body via the arm-leg rope linkage. This effectively decreased the muscular and mechanical demands placed on the legs, reducing the propulsive impulse by 43% (p < 0.001), which led to a 17% net reduction in the metabolic power required for walking (p = 0.001). Conclusions These findings provide the biomechanical and energetic basis for how we might reimagine the use of the arms in gait rehabilitation, opening the opportunity to explore if such a method could help patients regain their walking ability. Trial registration: Study registered on 09/29/2018 in ClinicalTrials.gov (ID—NCT03689647).

Metabolic Effects of Acute Hyperketonaemia in Man before and during An Hyperinsulinaemic Euglycaemic Clamp

1994 ◽  
Vol 86 (6) ◽  
pp. 677-687 ◽  
Author(s):  
J. Webber ◽  
E. Simpson ◽  
H. Parkin ◽  
I. A. MacDonald
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Oxidation ◽  
Respiratory Exchange Ratio ◽  
Saline Infusion ◽  
Metabolic Effects ◽  
Whole Body ◽  
Glucose Storage ◽  
Adipose Tissue Lipolysis ◽  
Subcutaneous Abdominal Adipose Tissue

1. The effects of acutely raising blood ketone body levels to those seen after 72 h of starvation were examined in 10 subjects after an overnight fast. Metabolic rate and respiratory exchange ratio were measured with indirect calorimetry before and during an insulin—glucose clamp. Arteriovenous differences were measured across forearm and subcutaneous abdominal adipose tissue. 2. In response to the clamp the respiratory exchange ratio rose from 0.82 to 0.83 during 3-hydroxybutyrate infusion and from 0.83 to 0.94 during control (saline) infusion (P < 0.001). 3. Forearm glucose uptake at the end of the clamp was 4.02 ± 0.95 (3-hydroxybutyrate infusion) and 7.09 ± 1.24 mmol min−1 100 ml−1 forearm (saline infusion). Whole body glucose uptake at the end of the clamp was 72.8 ± 7.9 (3-hydroxybutyrate infusion) and 51.0 ± 3.0 (saline infusion) mmol min−1 kg−1 body weight−1. 4. 3-Hydroxybutyrate infusion reduced the baseline abdominal venous—arterialized venous glycerol difference from 84 ± 28 to 25 ± 12 mmol/l and the non-esterified fatty acid difference from 0.60 ± 0.17 to 0.02 ± 0.09 mmol/l (P < 0.05 versus saline infusion). 5. Hyperketonaemia reduces adipose tissue lipolysis and decreases insulin-mediated forearm glucose uptake. Hyperketonaemia appears to prevent insulin-stimulated glucose oxidation, but does not reduce insulin-mediated glucose storage.

Molecular liver fingerprint reflects the seasonal physiology of the grey mouse lemur (Microcebus murinus) during winter

2021 ◽  
Author(s):  
Blandine Chazarin ◽  
Margaux Benhaim-Delarbre ◽  
Charlotte Brun ◽  
Aude Anzeraey ◽  
Fabrice Bertile ◽  
...  
Keyword(s):  
Glucose Intolerance ◽  
Molecular Mechanisms ◽  
Mouse Lemur ◽  
Primate Species ◽  
Whole Body ◽  
Microcebus Murinus ◽  
Late Winter ◽  
Pathological State ◽  
Fat Reserves ◽  
Mouse Lemurs

Grey mouse lemurs (Microcebus murinus) are a primate species exhibiting strong physiological seasonality in response to environmental energetic constraint. They notably store large amounts of lipids during early winter (EW), which are thereafter mobilized during late winter (LW), when food availability is low. In addition, they develop glucose intolerance in LW only. To decipher how the hepatic mechanisms may support such metabolic flexibility, we analyzed the liver proteome of adult captive male mouse lemurs, which seasonal regulations of metabolism and reproduction are comparable to their wild counterparts, during the phases of either constitution or use of fat reserves. We highlight profound changes that reflect fat accretion in EW at the whole-body level, however, without triggering an ectopic storage of fat in the liver. Moreover, molecular regulations would be in line with the lowering of liver glucose utilization in LW, and thus with reduced tolerance to glucose. However, no major regulation was seen in insulin signaling/resistance pathways, which suggests that glucose intolerance does not reach a pathological stage. Finally, fat mobilization in LW appeared possibly linked to reactivation of the reproductive system and enhanced liver detoxification may reflect an anticipation to return to summer levels of food intake. Altogether, these results show that the physiology of mouse lemurs during winter relies on solid molecular foundations in liver processes to adapt fuel partitioning while avoiding reaching a pathological state despite large lipid fluxes. This work emphasizes how the mouse lemur is of primary interest for identifying molecular mechanisms relevant to biomedical field.

MO332THE IRRADIATION-INDUCED RENAL ISCHEMIC PRECONDITIONING IS BLUNTED BY THE ORAL ADMINISTRATION OF THE ANTI-ANGIOGENIC AGENT, SUNITINIB

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Badr Khbouz ◽  
François Lallemand ◽  
Pascal Rowart ◽  
Laurence Poma ◽  
Agnès Noel ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Real Time ◽  
Ischemic Preconditioning ◽  
Functional Enrichment ◽  
Whole Body ◽  
Control Group ◽  
Mrna Levels ◽  
Wild Type ◽  
Post Irradiation ◽  
Real Time Qpcr

Abstract Background and Aims Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the pathways involved in kidney-centered irradiation. Next, we assess the functional and structural impact of kidney-centered irradiation applied before ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the neo-angiogenesis prevents irradiation-associated RIP. Method Experiment 1: Unilateral irradiation of the left kidney (8.56 Gy) was performed in male 10-week-old wild-type C57bl/6 mice (n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative high-throughput RNA-Seq (using BaseSpace Sequence Hub Illumina). Functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Experiment 2: Two x-ray beams (225Kv, 13mA) specifically targeted both kidneys for a total dose of 8.56Gy. The right kidneys were removed and harvested, and the left kidneys undergo 30-minute ischemia followed by 48-hour reperfusion (n=8) at Days 7-14-21-28 post irradiation. Experiment 3: Following the same protocol of renal I/R at Day14, 3 groups of male 10-week-old wild-type C57bl/6 mice were compared (n=8 per group): 1/ bilateral pre-irradiation; 2/ bilateral pre-irradiation and gavage with Sunitinib from Day2 to Day13; 3/ control group without irradiation or gavage. Results Experiment 1: Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B). Expressions of angiogenesis markers (CD31, TGFb1, HMOX1) showed an increase at both mRNA (real-time qPCR) and protein (immuno-staining) levels in irradiated kidneys compared to controls (p&lt;0.01). Experiment 2: Following I/R, the blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly lower in the irradiated animals compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p&lt;0.01). The renal infiltration by CD11b-positive cells (187±32 vs. 477±20/mm²) and F4-80 macrophages (110±22 vs. 212±25/mm²) was significantly reduced in the irradiated group. The real-time qPCR mRNA levels of the angiogenic markers, TGFb1 and CD31, were significantly increased in the irradiated group compared to controls (p&lt;0,01). The CD31-immunostating (quantified by FiJi) was increased in irradiated mice compared to controls (p&lt;0.01). Experiment 3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, the serum levels of BUN and SCr were lower in irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p&lt;0.01). No difference was observed between the irradiated-exposed mice to Sunitinib and the controls. Conclusion Renal irradiation induces the activation of signaling pathways involved in angiogenesis in mice. Renal pre-irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP.

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