Physiol Endocrinol Metab Research Articles

Molecular and functional characterization of human bone marrow adipocytes

Adipocytes are a cell population largely located in the human bone marrow cavity. In this specific microenvironment where adipocytes can interact with a variety of different cells, the role of fat is mainly unknown. To our knowledge, this report is the first to characterize mature adipocytes isolated from human bone marrow (BM-A) molecularly and functionally to better understand their roles into the hematopoietic microenvironment. Healthy BM-A were isolated after collagenase digestion and filtration. We studied the morphology of BM-A, their gene expression and immunophenotypic profile and their functional ability in the hematopoietic microenvironment, comparing them with adipocytes derived from adipose tissue (AT-A). BM-A showed a unilocular lipid morphology similar to AT-A and did not lose their morphology in culture; they showed a comparable pattern of stem cell-surface antigens to AT-A. In line with these observations, molecular data showed that BM-A expressed some embryonic stem cells genes, such as Oct4, KLf4, c-myc, Gata4, Tbx1, and Sox17, whereas they did not express the stem cell markers Sox2 and Nanog. Moreover, BM-A had long telomeres that were similar to bone marrow mesenchymal stem cells. Notably, BM-A supported the survival and differentiation of hematopoietic stem cells in long-term cultures. These results showed that BM-A are stromal cells with a gene expression pattern that distinguished them from AT-A. BM-A showed stem cell properties through their hematopoietic supporting function, which was certainly linked to their role in the maintenance of the bone marrow microenvironment. Depending on specific demands, BM-A may acquire different functions based on their local environment.

Corrigendum

CorrigendaCorrigendumPublished Online:15 Dec 2012https://doi.org/10.1152/ajpendo.zh1-6724-corr.2011Original articleMoreSectionsPDF (48 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Volume 302, April 2012Shen H, Shao M, Cho KW, Wang S, Chen Z, Sheng L, Wang T, Liu Y, Rui L. Herbal constituent sequoyitol improves hyperglycemia and glucose intolerance by targeting hepatocytes, adipocytes, and β-cells. Am J Physiol Endocrinol Metab 302: , 2012. First published April 15, 2012 302: E932–E940; published ahead of print January 31, 2012, doi:10.1152/ajpendo.00479.2011; http://ajpendo.physiology.org/cgi/content/full/302/04/E932.In this article, it was inadvertantly omitted that Y. Liu and L. Rui had contributed equally to the study.This article has no references to display. Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationRelated ArticlesHerbal constituent sequoyitol improves hyperglycemia and glucose intolerance by targeting hepatocytes, adipocytes, and β-cells 15 Apr 2012American Journal of Physiology-Endocrinology and Metabolism More from this issue > Volume 303Issue 12December 2012Pages E1504-E1504 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/ajpendo.zh1-6724-corr.2011History Published online 15 December 2012 Published in print 15 December 2012 Metrics

Mitochondrial ROS and muscle glucose uptake during exercise in transgenic mice

much research has examined the factors regulating skeletal muscle glucose uptake during exercise. Part of the impetus for this work has been to describe and understand the effects of regular physical activity (i.e., exercise training) on muscle glucose uptake and energy substrate partitioning,

Role of TRIB3 in regulation of insulin sensitivity and nutrient metabolism during short-term fasting and nutrient excess

We have suggested previously that Tribbles homolog 3 (TRIB3), a negative regulator of Akt activity in insulin-sensitive tissues, could mediate glucose-induced insulin resistance in muscle under conditions of chronic hyperglycemia (Liu J, Wu X, Franklin JL, Messina JL, Hill HS, Moellering DR, Walton RG, Martin M, Garvey WT. Am J Physiol Endocrinol Metab 298: E565-E576, 2010). In the current study, we have assessed short-term physiological regulation of TRIB3 in skeletal muscle and adipose tissues by nutrient excess and fasting as well as TRIB3's ability to modulate glucose transport and mitochondrial oxidation. In Sprague-Dawley rats, we found that short-term fasting enhanced insulin sensitivity concomitantly with decrements in TRIB3 mRNA (66%, P < 0.05) and protein (81%, P < 0.05) in muscle and increments in TRIB3 mRNA (96%, P < 0.05) and protein (~10-fold, P < 0.05) in adipose tissue compared with nonfasted controls. On the other hand, rats fed a Western diet for 7 days became insulin resistant concomitantly with increments in TRIB3 mRNA (155%, P < 0.05) and protein (69%, P = 0.0567) in muscle and a decrease in the mRNA (76%, P < 0.05) and protein (70%, P < 0.05) in adipose. In glucose transport and mitochondria oxidation studies using skeletal muscle cells, we found that stable TRIB3 overexpression impaired insulin-stimulated glucose uptake without affecting basal glucose transport and increased both basal glucose oxidation and the maximal uncoupled oxygen consumption rate. With stable knockdown of TRIB3, basal and insulin-stimulated glucose transport rates were increased, whereas basal glucose oxidation and the maximal uncoupled oxygen consumption rate were decreased. In conclusion, TRIB3 impacts glucose uptake and oxidation oppositely in muscle and fat according to levels of nutrient availability. The above data for the first time implicate TRIB3 as a potent physiological regulator of insulin sensitivity and mitochondrial glucose oxidation under conditions of nutrient deprivation and excess.

Shuttling glucose across brain microvessels, with a little help from GLUT1 and AMP kinase. Focus on “AMP kinase regulation of sugar transport in brain capillary endothelial cells during acute metabolic stress”

The Blood-Brain Barrier: a Gatekeeper of Brain “Individuality” The blood-brain barrier (BBB) maintains the individuality of brain fluid, while allowing it to selectively import nutrients and process toxic products. Its major constituent is a single layer of continuous, nonfenestrated endothelium lining the microvessels, whose unique features account in large part for the integrity of the barrier. The endothelial cell monolayer is the major determinant, but other cells in the central nervous system (e.g., pericytes and astrocytes) contribute to the integrity of the BBB. The interendothelial tight junctions of the BBB are one of its signature elements that greatly restrict paracellular permeability to solutes, fluid, and transmigrating cells. This is markedly distinct from the leakier, discontinuous, and fenestrated endothelium of liver microvessels (sinusoids). For example, the tight junctions of the cerebral endothelium (pial vessels) confer an electrical resistance (1,300 ·cm 2 ) far higher than other endothelia (6). Therefore, communication between blood and the brain interstitial fluid requires individually tailored molecular mechanisms. Transcytosis is the movement of molecules through a cellular barrier. Whereas proteins can traverse through vesicular carrier processes that could carry solutes through fluid phase endocytosis, the brain microvasculature is uniquely poor in plasmalemmal and cytoplasmic caveolae (1). Instead, bidirectional passage of small molecules across the BBB is stringently regulated by numerous transporters and receptors. These typically work in tandem across the luminal and abluminal membranes of the endothelial cell.

The effect of frequent hemodialysis on nutrition and body composition: Frequent Hemodialysis Network Trial

We investigated the effects of frequency of hemodialysis on nutritional status by analyzing the data in the Frequent Hemodialysis Network Trial. We compared changes in albumin, body weight and composition among 245 patients randomized to 6- or 3-times per week in-center hemodialysis (Daily Trial) and 87 patients randomized to 6-times per week nocturnal or 3-times per week conventional hemodialysis, performed largely at home (Nocturnal Trial). In the Daily Trial, there were no significant differences between groups in changes in serum albumin or the equilibrated protein catabolic rate by 12 months. There was a significant relative decrease in pre-dialysis body weight of 1.5 ± 0.2 kg in the 6 times per week group at one month, but this significantly rebounded by 1.3 ± 0.5 kg over the remaining 11 months. Extracellular water decreased in the 6 times per week compared to the 3 per week hemodialysis group. There were no significant between-group differences in phase angle, intracellular water or body cell mass. In the Nocturnal Trial, there were no significant between-group differences in any study parameter. Any gain in “dry” body weight corresponded to increased adiposity rather than muscle mass but was not statistically significant. Thus, frequent in-center hemodialysis reduced extracellular water but did not increase serum albumin or body cell mass while frequent nocturnal hemodialysis yielded no net effect on parameters of nutritional status or body composition.

Response of C57Bl/6 mice to a carbohydrate-free diet

High fat feeding in rodents generally leads to obesity and insulin resistance whereas in humans this is only seen if dietary carbohydrate is also high, the result of the anabolic effect of poor regulation of glucose and insulin. A previous study of C57Bl/6 mice (Kennedy AR, et al.: Am J Physiol Endocrinol Metab (2007) 262 E1724-1739) appeared to show the kind of beneficial effects of calorie restriction that is seen in humans but that diet was unusually low in protein (5%). In the current study, we tested a zero-carbohydrate diet that had a higher protein content (20%). Mice on the zero-carbohydrate diet, despite similar caloric intake, consistently gained more weight than animals consuming standard chow, attaining a dramatic difference by week 16 (46.1 ± 1.38 g vs. 30.4 ± 1.00 g for the chow group). Consistent with the obese phenotype, experimental mice had fatty livers and hearts as well as large fat deposits in the abdomino-pelvic cavity, and showed impaired glucose clearance after intraperitoneal injection. In sum, the response of mice to a carbohydrate-free diet was greater weight gain and metabolic disruptions in distinction to the response in humans where low carbohydrate diets cause greater weight loss than isocaloric controls. The results suggest that rodent models of obesity may be most valuable in the understanding of how metabolic mechanisms can work in ways different from the effect in humans.

Viewpoint: Are there valid concerns for completing a marathon at 39 weeks of pregnancy?

recently, widespread media attention has been given to Amber Danielle Miller, a 27-yr-old woman (163 cm tall), who, at 39 wk of pregnancy, gave birth following her completion of the Chicago Marathon on October 9, 2011 ([17][1], [19][2], [21][3]). She completed the Marathon in 6 h, 25 min, and 50 s

Utilizing the hair follicle to dissect the regulation and autocrine/paracrine activities of prolactin in humans

to the editor: Ferraris et al. ([4][1]) have recently reported an increase in anterior pituitary cell proliferation in Δ1-9-G129R-hPRL (competitive prolactin receptor antagonist) -expressing transgenic mice compared to wild-type controls. In addition, they reported increased proliferation/decreased

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

the year 2012 marks the 125th anniversary of the American Physiological Society (APS). Throughout its history, APS has been a leader in innovation and excellence in scientific technology, discovery, education, and publication. Consistent with this history, APS is leading the scientific publication

Alteration of lipids and the transcription of lipid-related genes in myelodysplastic syndromes via a TP53-related pathway

Myelodysplastic syndromes (MDS) are clonal stem cell diseases of the bone marrow characterized by abnormalities in maturation of hematopoietic cells of all lineages. MDS patients frequently have lower lipids and high rates of apoptosis and p53 (TP53) expression. An association between the reduced lipids in MDS and the expression of lipid-related genes was sought. We further evaluated whether 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGcoAR) and low-density lipoprotein receptor (LDL-R) are regulated by TP53 invivo and invitro. Gene expression was measured using real-time reverse transcription polymerase chain reaction on RNA extracted from bone marrow and peripheral blood from eight newly diagnosed MDS patients and eight controls and from mice livers. Serum lipid profile was measured using colorimetric enzymatic procedures. Total- and LDL cholesterol were lower in MDS patients in comparison to controls (p = 0.04 and p = 0.01, respectively). HMGcoAR messenger RNA increased in peripheral blood and bone marrow of MDS patients compared to controls (p = 0.04 and p = 0.01, respectively). LDL-R messenger RNA was higher only in the peripheral blood of MDS patients (p = 0.05). Comparable results were obtained invivo. The transcription of these genes correlates with TP53 activation as documented by p21 messenger RNA elevation, a surrogate for TP53 activation and by using TP53 temperature-sensitive cells treated with adriamycin. To conclude, an association between reduced lipids in MDS and expression of HMGcoAR and LDL-R genes was documented. The transcription of these genes can be regulated by TP53.

Role of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications

As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients.

Response of C57Bl/6 mice to a carbohydrate-free diet

High fat feeding in rodents generally leads to obesity and insulin resistance whereas in humans this is only seen if dietary carbohydrate is also high, the result of the anabolic effect of poor regulation of glucose and insulin. A previous study of C57Bl/6 mice (Kennedy AR, et al.: Am J Physiol Endocrinol Metab (2007) 262 E1724-1739) appeared to show the kind of beneficial effects of calorie restriction that is seen in humans but that diet was unusually low in protein (5%). In the current study, we tested a zero-carbohydrate diet that had a higher protein content (20%). Mice on the zero-carbohydrate diet, despite similar caloric intake, consistently gained more weight than animals consuming standard chow, attaining a dramatic difference by week 16 (46.1 ± 1.38 g vs. 30.4 ± 1.00 g for the chow group). Consistent with the obese phenotype, experimental mice had fatty livers and hearts as well as large fat deposits in the abdomino-pelvic cavity, and showed impaired glucose clearance after intraperitoneal injection. In sum, the response of mice to a carbohydrate-free diet was greater weight gain and metabolic disruptions in distinction to the response in humans where low carbohydrate diets cause greater weight loss than isocaloric controls. The results suggest that rodent models of obesity may be most valuable in the understanding of how metabolic mechanisms can work in ways different from the effect in humans.

Retraction

Gómez-Hernández A, de las Heras N, Otero YF, Escribano Ó, Gozalbo-López B, Guillén C,Cachofeiro V, Lahera V, Benito M. Differential vascular damage in non-compensated versus compensated insulin resistance. Am J Physiol Endocrinol Metab (First published May 10, 2011).doi:10.1152/ajpendo.00662.2010.This article is being retracted by the American Physiological Society at the request of the authors because it contains improperly prepared data in Figures 3A and 4B. The authors apologize to the readers for this error and for any inconvenience associated with the publication of the article.

Reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Blocks Transfer of [2Fe-2S] Clusters from MitoNEET to an Apo-Acceptor Protein

MitoNEET is the founding member of the recently discovered CDGSH family of [2Fe-2S] proteins. Its structure contains a unique homodimeric fold with each monomer containing one [2Fe-2S] cluster (1). MitoNEET is a target of the thiazolidinedione (TZD) class of anti-diabetes drugs (2). Recently, it was reported that the [2Fe-2S] cluster in mitoNEET is destabilized upon binding of NADPH/NADP+ (3). As mitoNEET is capable of transferring its [2Fe-2S] clusters to an apo-acceptor protein (4) and an obvious question to ask is whether NADPH binding accelerates or abrogates cluster transfer. We show that NADPH blocks transfer of mitoNEET's [2Fe-2S] cluster to an apo-acceptor protein (see Figure). This suggests a likely functional role for the mitoNEET:NADPH/NADP+ interaction.(1) Paddock ML et al. (2007) PNAS 104 14342-7(2) Colca JR et al. (2004) Am J Physiol Endocrinol Metab 286 E252-60(3) Zhou et al. (2010) Biochemistry 49 9604-12(4) Zuris JA et al. (2011) PNAS 108 13047-52∗Supported by the Heme and Blood Proteins Training Grant 5T32DK007233-34View Large Image | View Hi-Res Image | Download PowerPoint Slide

Does PCOS have developmental origins?

PRO--The similarity of reproductive and metabolic phenotype between prenatally androgenized sheep, or monkeys, and women with PCOS provides strong supportive evidence for developmental programming being important in the etiology of PCOS. CON--While one would not exclude altogether developmental determinants of PCOS, it is difficult to view PCOS as purely developmental or resulting only from intrauterine exposures or simply an adaptation gone astray.