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The Pituitary Is a Candidate Organ That Modulates Circulating Klotho Levels.

ABSTRACT: Context:The antiaging protein Klotho is shed and released into the blood stream (soluble Klotho). Growth hormone (GH) is considered an active Klotho regulator, because growth retardation is described in Klotho-deficient mice. The origin of circulating Klotho is, however, not fully understood. Objectives:Our objective was to analyze a possible role of the pituitary in regulating soluble Klotho in patients with pituitary adenomas. Patients Design and Setting:We analyzed serum levels of soluble Klotho, GH, and insulin-like growth factor 1 (IGF-1) from 21 consecutive patients in our center with pituitary tumor, 7 with GH-producing adenomas (GHomas), and 14 with non-GH-producing pituitary adenomas (non-GHomas), before and after endoscopic transsphenoidal surgery (eTSS). Main Outcome Measure:Soluble Klotho levels were determined by ELISA with antihuman Klotho antibodies. Results:Baseline soluble Klotho levels in all patients, those with GHoma and those with non-GHoma, were 542 (median) (interquartile range: 403, 652), 1083 (425, 1213), and 525 (399, 590), respectively. A drastic reduction in Klotho levels was identified in those with GHoma, accompanied by decreases in GH and IGF-1 levels, after eTSS. Interestingly, patients with non-GHoma had significant declines in soluble Klotho without any significant changes in GH levels. Moreover, an oral glucose tolerance test revealed that soluble Klotho levels decreased, whereas a paradoxical GH peak was observed after glucose intake in a patient with GHoma. Conclusions:Our data suggest that the pituitary may be a key organ that regulates circulating Klotho concentrations, implying that the pituitary possibly controls circulating Klotho through GH-dependent and/or GH-independent mechanisms.

SUBMITTER: Sato T

PROVIDER: S-EPMC6344344 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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The Pituitary Is a Candidate Organ That Modulates Circulating Klotho Levels.

Sato Tetsuhiko T Komaba Hirotaka H Nagatani Tetsuya T Watanabe Tadashi T Kishida Yugo Y Fukagawa Masafumi M

Journal of the Endocrine Society 20181114 1

<h4>Context</h4>The antiaging protein Klotho is shed and released into the blood stream (soluble Klotho). Growth hormone (GH) is considered an active Klotho regulator, because growth retardation is described in Klotho-deficient mice. The origin of circulating Klotho is, however, not fully understood.<h4>Objectives</h4>Our objective was to analyze a possible role of the pituitary in regulating soluble Klotho in patients with pituitary adenomas.<h4>Patients design and setting</h4>We analyzed serum ...[more]

PMID: 30697600

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Project description:ObjectiveOur laboratory recently identified the centrally circulating ?-klotho protein as a novel hypothalamic regulator of food intake and glucose metabolism in mice. The current study aimed to investigate novel molecular effectors of central ?-klotho in the arcuate nucleus of the hypothalamus (ARC), while further deciphering its role regulating energy balance in both humans and mice.MethodsCerebrospinal fluid (CSF) was collected from 22 adults undergoing lower limb orthopedic surgeries, and correlations between body weight and ?-klotho were determined using an ?-klotho enzyme-linked immunosorbent assay (ELISA) kit. To investigate the effects of ?-klotho on energy expenditure (EE), 2-day intracerebroventricular (ICV) treatment was performed in diet-induced obesity (DIO) mice housed in TSE Phenomaster indirect calorimetry metabolic cages. Immunohistochemical staining for cFOS and patch clamp electrophysiology were used to determine the effects of central ?-klotho on proopiomelanocortin (POMC) and tyrosine hydroxylase (TH) neurons. Additional stainings were performed to determine novel roles for central ?-klotho to regulate non-neuronal cell populations in the ARC. Lastly, ICV pretreatment with fibroblast growth factor receptor (FGFR) or PI3kinase inhibitors was performed to determine the intracellular signaling involved in ?-klotho-mediated regulation of ARC nuclei.ResultsObese/overweight human subjects had significantly lower CSF ?-klotho concentrations compared to lean counterparts (1,044 ± 251 vs. 1616 ± 218 pmol/L, respectively). Additionally, 2 days of ICV ?-klotho treatment increased EE in DIO mice. ?-Klotho had no effects on TH neuron activity but elicited varied responses in POMC neurons, with 44% experiencing excitatory and 56% experiencing inhibitory effects. Inhibitor experiments identified an ?-klotho?FGFR?PI3kinase signaling mechanism in the regulation of ARC POMC and NPY/AgRP neurons. Acute ICV ?-klotho treatment also increased phosphorylated ERK in ARC astrocytes via FGFR signaling.ConclusionOur human CSF data provide the first evidence that impaired central ?-klotho function may be involved in the pathophysiology of obesity. Furthermore, results in mouse models identify ARC POMC neurons and astrocytes as novel molecular effectors of central ?-klotho. Overall, the current study highlights prominent roles of ?-klotho?FGFR?PI3kinase signaling in the homeostatic regulation of ARC neurons and whole-body energy balance.

Project description:The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels. Plasma α-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (P < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn's disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [-0.198 (-0.332, -0.063)] on α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability.

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The Pituitary Is a Candidate Organ That Modulates Circulating Klotho Levels.

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The Pituitary Is a Candidate Organ That Modulates Circulating Klotho Levels.

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