Abstract
Background
Circulating sex hormones exert unique effects on metabolism, leading to sexual dimorphism in white adipose tissue distribution and function. The gender affirming hormone therapy ...(GAHT) or cross-sex hormone therapy (CSHT) for transgender patients lower the endogenous sex hormones while raising the opposite sex hormones. Sex hormones are known to have a significant impact on white adipose tissue and metabolism. However, long-term metabolic changes with GAHT in transgender individuals have not been studied, nor are the underlying mechanisms properly elucidated.
Hypothesis
We test the hypothesis that GAHT will result in sexual dimorphic changes in morphology and function of white adipose tissue according to the type of sex hormones used and the native sex of the patients.
Aim 1
To study the effect of cross-sex hormones on clinical parameters such as blood pressure, weight, waist-hip circumference ratio, serum lipids, insulin sensitivity
Aim 2
To study the changes in human subcutaneous white adipose tissue (SWAT) distribution and expansion with GAHT
Aim 3
To study changes in circulating metabolites and adipokines, and pro-inflammatory and pro-fibrotic gene expression in SWAT with GAHT.
Methodology
31 hormone-naive patients (19 Male-to-Female; MtF and 12 Female-to-Male; FtM) were enrolled in the longitudinal study and followed up for 3 years. Clinical parameters and blood samples were gathered at baseline and at 6 month intervals. DXA scans and fat biopsies (peri-umbilical SWAT) were performed at baseline and at 1 year intervals.
Results
The results presented here compare baseline and at 1 year of GAHT. There was an increase in total cholesterol in the MtF group. HOMA-IR, total fat mass and visceral fat mass increased in MtF group, while they decreased in the FtM group. In MtF group, lean mass and bone mineral content (BMC) decreased at 1 year, but no change was observed in the FtM group. On histological assessment, fat cell size increased in MtF group, while it decreased in the FtM group.
Conclusion
In MtF transgender patients, androgen deprivation and estrogen treatment resulted in reduced insulin sensitivity together with a rise in total cholesterol possibly via a decrease in lean mass and adipose tissue expansion through significant adipocyte hypertrophy. In FtM transgender patients, testosterone treatment caused improved insulin sensitivity possibly via a decrease in total and visceral fat mass. The greatest strengths of our project include its longitudinal nature over 3 years to capture long-term effects in the same patients as well as deeper mechanistic insights into the underlying metabolite, adipokine and gene expression changes. The limitations of our study include the small sample size with heterogeneity of study population in terms of demographics and lifestyles.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
Adipose tissue, diabetes and Chagas disease Tanowitz, Herbert B; Jelicks, Linda A; Machado, Fabiana S ...
Advances in Parasitology,
2011, Letnik:
76
Journal Article, Book Chapter
Recenzirano
Odprti dostop
Adipose tissue is the largest endocrine organ in the body and is composed primarily of adipocytes (fat cells) but also contains fibroblasts, endothelial cells, smooth muscle cells, macrophages and ...lymphocytes. Adipose tissue and the adipocyte are important in the regulation of energy metabolism and of the immune response. Adipocytes also synthesize adipokines such as adiponectin which is important in the regulation of insulin sensitivity and inflammation. Infection of mice with Trypanosoma cruzi results in an upregulation of inflammation in adipose tissue that begins during the acute phase of infection and persists into the chronic phase. The adipocyte is both a target of infection and a reservoir for the parasite during the chronic phase from which recrudescence of the infection may occur during periods of immunosuppression.
Scavenger receptors are integral membrane proteins that mediate the endocytosis of modified lipoproteins. The first of these to be purified and cloned were the type I and II macrophage scavenger ...receptors (SR-AI and SR-AII; class A scavenger receptors). Subsequently, the cell surface protein CD36 was shown to bind oxidized low density lipoprotein (oxidized LDL). From a Chinese hamster ovary (CHO) cell variant we have cloned by expression the cDNA for a new member of the CD36 family of membrane proteins, SR-BI, whose predicted protein sequence of 509 amino acids is approximately 30% identical to those of the four previously identified family members. Both SR-BI and CD36 displayed high affinity binding for acetylated LDL with an apparent dissociation constant on the order of approximately 5 micrograms of protein/ml. The ligand binding specificities of CD36 and SR-BI, determined by direct binding or competition assays, were similar, but not identical; both bind modified proteins (acetylated LDL, oxidized LDL, maleylated bovine serum albumin), but not the broad array of other polyanions (e.g. fucoidin, polyguanosinic acid, carrageenan) which are ligands of the class A receptors. Thus, SR-BI and CD36 define a second class of scavenger receptors, designated class B. Native LDL, which does not bind to either class A receptors or CD36, unexpectedly bound with high affinity to SR-BI. Northern blot analysis of murine tissues showed that SR-BI was most abundantly expressed in fat and was present at moderate levels in lung and liver. Furthermore, SR-BI mRNA expression was induced upon differentiation of 3T3-L1 cells into adipocytes. Thus, the tissue distribution of expression and ligand binding properties of SR-BI raise the possibility that this cell surface receptor may play an important role in lipid metabolism.
Pantophysin, a protein related to the neuroendocrine-specific synaptophysin, recently has been identified in non-neuronal tissues. In the present study, Northern blots showed that pantophysin mRNA ...was abundant in adipose tissue and increased during adipogenesis of 3T3-L1 cells. Immunoblot analysis of subcellular fractions showed pantophysin present exclusively in membrane fractions and relatively evenly distributed in the plasma membrane and internal membrane fractions. Sucrose gradient ultracentrifugation demonstrated that pantophysin and GLUT4 exhibited overlapping distribution profiles. Furthermore, immunopurified GLUT4 vesicles contained pantophysin, and both GLUT4 and pantophysin were depleted from this vesicle population following treatment with insulin. Additionally, a subpopulation of immunopurified pantophysin vesicles contained insulin-responsive GLUT4. Consistent with the interaction of synaptophysin with vesicle-associated membrane protein 2 in neuroendocrine tissues, pantophysin associated with vesicle-associated membrane protein 2 in adipocytes. Furthermore, in 32Porthophosphate-labeled cells, pantophysin was phosphorylated in the basal state. This phosphorylation was unchanged in response to insulin; however, insulin stimulated the phosphorylation of a 77-kDa protein associated with α-pantophysin immunoprecipitates. Although the functional role of pantophysin in vesicle trafficking is unclear, its presence on GLUT4 vesicles is consistent with the emerging role of solubleN-ethylmaleimide-sensitive protein receptor (SNARE) factor complex and related proteins in regulated vesicle transport in adipocytes. In addition, pantophysin may provide a marker for the analysis of other vesicles in adipocytes.
Abstract Hypoxia-inducible factor-1alpha (HIF-1alpha) in adipose tissue is known to promote obesity. We hypothesized that HIF-1alpha interferes with brown fat thermogenesis, thus decreasing energy ...expenditure. To test this hypothesis, we compared transgenic mice constitutively expressing HIF-1alpha in adipose tissues (HIF-1alpha++) at usual temperature (22 °C), where brown fat is somewhat active, or at thermoneutrality (30 °C), where brown fat is minimally active. HIF-1alpha++ mice or control litter mates were separated into room temperature (22 °C) or thermoneutrality (30 °C) groups. We assessed weight gain, food intake, calorimetry, activity, and oxygen consumption and transcriptional changes in isolated white and brown adipocytes. At 22 °C, HIF-1alpha++ mice exhibited accelerated weight gain, cold and glucose intolerance, hyperglycemia, and decreased energy expenditure without changes in food intake or activity. These changes were absent or minimal at thermoneutrality. In brown adipocytes of HIF-1alpha++ mice, oxygen consumption decreased ~50 % in association with reduced mitochondrial content, uncoupling protein 2, and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1alpha). In conclusion, adipose HIF-1alpha overexpression inhibits thermogenesis and cellular respiration in brown adipose tissue, promoting obesity in the setting of reduced ambient temperature. Key message Constitutive HIF-1alpha activation in adipose tissue promotes weight gain in mice. The weight gain is associated with reduced brown adipose tissue function and oxygen consumption. Reduced oxygen consumption may be mediated by reductions in mitochondria.
The parasite Trypanosoma cruzi causes a persistent infection, Chagas disease, affecting millions of persons in endemic areas of Latin America. As a result of immigration, this disease has now been ...diagnosed in non-endemic areas worldwide. Although, the heart and gastrointestinal tract are the most studied, the insulin-secreting beta cell of the endocrine pancreas is also a target of infection. In this review, we summarize available clinical and laboratory evidence to determine whether T. cruzi-infection-mediated changes of beta cell function is likely to contribute to the development of hyperglycemia and diabetes. Our literature survey indicates that T. cruzi infection of humans and of experimental animals relates to altered secretory behavior of beta cells. The mechanistic basis of these observations appears to be a change in stimulus-secretion pathway function rather than the loss of insulin-producing beta cells. Whether this attenuated insulin release ultimately contributes to the pathogenesis of diabetes in human Chagas disease, however, remains to be determined. Since the etiologies of diabetes are multifactorial including genetic and lifestyle factors, the use of cell- and animal-based investigations, allowing direct manipulation of these factors, are important tools in testing if reduced insulin secretion has a causal influence on diabetes in the setting of Chagas disease. Long-term clinical investigations will be required to investigate this link in humans.
Caveolae are ∼50−100 nm invaginations of the plasma membrane thought to form as a result of a local accumulation of cholesterol, sphingolipids, and a unique family of three proteins known as the ...caveolins: Cav-1, -2, and -3. Here, we report the identification, sequence, and developmental expression of the three caveolin genes in the amphibian Xenopus laevis. Sequence comparisons show that Xenopus Cav-1, -2, and -3 are ∼80, 64, and 45% identical, respectively, to their counterparts in humans. Furthermore, Northern blotting experiments demonstrate that the Xenopus caveolins have tissue-specific expression profiles consistent with those previously reported in adult mammals. In the adult frog, Xenopus Cav-1 and Cav-2 are most abundantly expressed in the fat body and the lungs, while Xenopus Cav-3 is primarily expressed in muscle tissue types (heart and skeletal muscle). However, our temporal and spatial analyses of these expression patterns during embryogenesis reveal several novel features, with possible relevance to developmental signaling. Transcripts encoding Xenopus Cav-1 and -2 first appear in the notochord of neurula stage embryos, which represents a key signaling tissue. In contrast, Xenopus Cav-3 shows a highly specific punctate expression pattern in the embryonic epidermis, similar to previous patterns implicated in Notch signaling. These findings are in striking contrast to their steady-state expression patterns in the adult frog. Taken together, our results show that the Xenopus caveolin gene family is present and differentially expressed in both embryonic and adult tissues. This report is the first detailed study of caveolin gene expression in a developing embryo.
Obesity is a leading cause of preventable death and morbidity. To elucidate the mechanisms connecting metabolically active brown adipose tissue (BAT) and metabolic health may provide insights into ...methods of treatment for obesity-related conditions.
F-fluorodeoxyglucose positron emission tomography/computed tomography (
FDG-PET/CT) is traditionally used to image human BAT activity. However, the primary energy source of BAT is derived from intracellular fatty acids and not glucose. Beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) is a fatty acid analogue amenable to in vivo imaging by single photon emission computed tomography/CT (SPECT/CT) when radiolabeled with iodine isotopes. In this study, we compare the use of
FDG-PET/CT and
I-BMIPP-SPECT/CT for fat imaging to ascertain whether BMIPP is a more robust candidate for the non-invasive evaluation of metabolically active adipose depots. Interscapular BAT, inguinal white adipose tissue (iWAT), and gonadal white adipose tissue (gWAT) uptake of
FDG and
I-BMIPP was quantified in mice following treatment with the BAT-stimulating drug CL-316,243 or saline vehicle control. After CL-316,243 treatment, uptake of both radiotracers increased in BAT and iWAT. The standard uptake value (SUV
) for
FDG and
I-BMIPP significantly correlated in these depots, although uptake of
I-BMIPP in BAT and iWAT more closely mimicked the fold-change in metabolic rate as measured by an extracellular flux analyzer. Herein, we find that imaging BAT with the radioiodinated fatty acid analogue BMIPP yields more physiologically relevant data than
FDG-PET/CT, and its conventional use may be a pivotal tool for evaluating BAT in both mice and humans.
Adiponectin has exhibited positive effects in regulation of systemic metabolism and insulin sensitivity through tissues such as liver, skeletal muscle, and centrally in the brain. Circulating as ...oligomers of 90 to 1080kDa, adiponectin must cross the endothelium to have metabolic effects. Our laboratory has reported differential efficacy of these oligomers on insulin sensitivity. Recent data has also demonstrated oligomer size‐dependence on adiponectin clearance. Only the small trimeric oligomer is found in cerebral spinal fluid. Here, we have measured the Stokes radii of adiponectin to be approximately 5, 10, and 25nm for the trimeric, hexameric, and high molecular weight (HMW) forms, respectively. The HMW size may present transport limitations across endothelial barriers in muscle or in the brain. Using murine 3B‐11, MS1, and bEnd3 endothelial cells in transwell permeability studies, we demonstrate that 3B‐11 and MS1 cells permit equivalent transport of trimeric and HMW adiponectin for their diffusive sizes. The bEnd3 cells, a model of brain endothelium, present an increased barrier to HMW adiponectin. In all cases, however, adiponectin fluxes were less than equivalently‐sized dextrans, suggesting the existence of active adiponectin transport mechanisms. These data demonstrate that the effects of different adiponectin oligomers on tissue metabolism may depend on the endothelium in a given tissue.
PDF
![Adipose HIF-1[alpha] causes...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0946-2716/small "Adipose HIF-1[alpha] causes obesity by suppressing brown adipose tissue thermogenesis")
