Altered Adipose Tissue Research Articles

Transgenic ω-3 PUFA enrichment alters morphology and gene expression profile in adipose tissue of obese mice: Potential role for protectins

ObjectiveDietary administration of ω-3 polyunsaturated fatty acids (PUFA) is often associated with altered adipose tissue (AT) morphology and/or function in obese mice. Yet, it is unclear whether this is an indirect consequence of reduced weight gain or results from direct actions of ω-3 PUFA. Here we studied the AT of high fat (HF)-fed fat-1 transgenic mice that convert endogenous ω-6 to ω-3 PUFA while maintaining equivalent fat accretion as their wild-type (WT) counterparts. Materials and methodsAdipocyte size profiling, Affymetrix microarray pathway analysis, qPCR and protectin identification and analysis were performed in epididymal AT from hemizygous fat-1(+/−) mice and their wild type littermates that had been fed a HF diet for 8weeks from 6weeks of age. ResultsDespite equivalent fat pad mass, we found that epididymal AT from HF-fed transgenic animals possesses fewer large and very large but more mid-size adipocytes compared to WT mice. In order to better understand the underlying mechanisms contributing to the observed alteration in adipocyte size we performed an Affymetrix microarray. Pathway analysis of these data highlighted adipogenesis, cholesterol biosynthesis, insulin signaling, prostaglandin synthesis/regulation and small ligand GPCRs as points where differentially expressed genes were significantly overrepresented. Observed changes were confirmed for four candidate genes: Cnr1, Cnr2, Faah and Pparg by qPCR. Finally we demonstrated that protectin DX is present in AT and that protectin DX and protectin D1 promote comparable PPARγ transcriptional activity. ConclusionsThese data provide unprecedented evidence that ω-3 PUFA coordinately regulate AT gene expression programs in a manner that is independent of restriction of weight gain or fat accrual and highlight an important influence of ω-3 PUFA on adipogenesis. Furthermore we provide primary evidence suggesting that protectins likely contribute to these effects via their influence on PPARγ.

Salsalate treatment improves glycemia without altering adipose tissue in nondiabetic obese hispanics.

ObjectiveSalsalate treatment has well-known effects on improving glycemia and the objective of this study was to examine whether the mechanism of this effect is related to changes in adipose tissue.MethodsWe conducted a randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years). The intervention consisted of 4 g/day of salsalate (n=11) versus placebo (n=13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.ResultsIn those receiving salsalate, plasma fasting glucose decreased by 3.4% (P<0.01), free fatty acids decreased by 42.5% (P=0.06) and adiponectin increased by 27.7% (P<0.01). Salsalate increased insulin AUC by 38% (P=0.01) and HOMA-B by 47.2% (P<0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P<0.01).ConclusionsOur findings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation.

Telomere length differences between subcutaneous and visceral adipose tissue in humans

Adipocyte hypertrophy and hyperplasia have been shown to be associated with shorter telomere length, which may reflect aging, altered cell proliferation and adipose tissue (AT) dysfunction. In individuals with obesity, differences in fat distribution and AT cellular composition may contribute to obesity related metabolic diseases. Here, we tested the hypotheses that telomere lengths (TL) are different between: (1) abdominal subcutaneous and omental fat depots, (2) superficial and deep abdominal subcutaneous AT (SAT), and (3) adipocytes and cells of the stromal vascular fraction (SVF). We further asked whether AT TL is related to age, anthropometric and metabolic traits.TL was analyzed by quantitative PCR in total human genomic DNA isolated from paired subcutaneous and visceral AT of 47 lean and 50 obese individuals. In subgroups, we analyzed TL in isolated small and large adipocytes and SVF cells.We find significantly shorter TL in subcutaneous compared to visceral AT (P < 0.001) which is consistent in men and subgroups of lean and obese, and individuals with or without type 2 diabetes (T2D). Shorter TL in SAT is entirely due to shorter TL in the SVF compared to visceral AT (P < 0.01). SAT TL is most strongly correlated with age (r = −0.205, P < 0.05) and independently of age with HbA1c (r = −0.5, P < 0.05). We found significant TL differences between superficial SAT of lean and obese as well as between individuals with our without T2D, but not between the two layers of SAT. Our data indicate that fat depot differences in TL mainly reflect shorter TL of SVF cells. In addition, we found an age and BMI-independent relationship between shorter TL and HbA1c suggesting that chronic hyperglycemia may impair the regenerative capacity of AT more strongly than obesity alone.

Telmisartan attenuates the inflamed mesenteric adipose tissue in spontaneous colitis by mechanisms involving regulation of neurotensin/microRNA-155 pathway

Mesenteric adipose tissue hypertrophy is unique to Crohn's disease while the molecular basis of the crosstalk between MAT and the intestinal inflammation is largely unknown. Telmisartan is an angiotensin II type 1 receptor blocker and a peroxisome proliferator-activated receptor-receptor-γ agonist which has beneficial effects on fat distribution and pro-inflammatory adipokine expression. We evaluated the effect of telmisartan upon mesenteric adipose tissue alterations and inflammatory features in IL-10−/− mice. We found that treatment with telmisartan significantly ameliorated the severity of colitis in IL-10−/− mice. Additionally, administration of telmisartan was associated with restoration of mesenteric adipose tissue adipocyte morphology and the expression of adipokines. Furthermore, telmisartan treatment suppressed the neurotensin/microRNA-155 pathway in mesenteric adipose tissue from spontaneous colitis which was confirmed by an in vitro study using cultured mesenteric adipose tissue from Crohn's disease patients. Administration of telmisartan showed promising results in spontaneous colitis which was associated with the attenuated mesenteric adipose tissue alteration which at least in part, was associated with its activity in the regulation of the neurotensin/microRNA-155 pathway. These results support the hypothesis that regulating the abnormal immune response in adipose tissue is an important target for the treatment of Crohn's disease.

Similar and additive effects of ovariectomy and diabetes on insulin resistance and lipid metabolism.

Type 2 diabetes mellitus (T2DM) is among the leading causes of death in postmenopausal women. The disruption of ovarian function may contribute to the incidence of T2DM. The purpose of this study was to investigate the effects of ovariectomy and T2DM on glucose and lipid homeostasis, perilipin levels in adipose tissues, as a lipolytic regulator, and levels of certain adipokines. Ovariectomized (OVX) rats were used as a model for postmenopausal women. The study was performed on sham, OVX, sham diabetic, and OVX diabetic female rats. The results indicated that ovariectomy alters adipose tissue metabolism through reducing perilipin content in white adipose tissue (WAT); however it has no effect on perilipin level in brown adipose tissue (BAT). OVX diabetic females suffer from serious metabolic disturbances, suggested by exacerbation of insulin resistance in terms of disrupted lipid profile, higher HOMA-IR, hyperinsulinemia, higher leptin, and lower adiponectin concentrations. These metabolic derangements may underlie the predisposition for cardiovascular disease in women after menopause. Therefore, for efficient treatment, the menopausal status of diabetic female should be addressed, and the order of events is of great importance because ovariectomy following development of diabetes has more serious complications compared to development of diabetes as result of menopause.

Cardiovascular risk in Egyptian healthy consumers of different types of combined oral contraceptives pills: A comparative study.

This study aimed to evaluate the associated cardiovascular risk in Egyptian healthy consumers of different types of combined oral contraceptives pills (COCPs) via determination of lipids profiles, Castelli index I, leptin, adiponectin, and resistin concentrations as cardiovascular risk factors. In this cross-sectional study, the study groups consisted of control group that represented by 30 healthy married women who were not on any contraceptive mean or any hormonal therapy and had normal menstrual cycles, group two consisted of 30 women who were users of Levonorgesterl 0.15 mg plus Ethinylestradiol 0.03 mg as 21 days cycle, group three consisted of 30 women who were users of Gestodene 0.075 mg plus Ethinylestradiol 0.03 mg as 21 days cycle, and group four consisted of 30 women who were users of Drospirenone 3 mg plus Ethinylestradiol 0.03 mg as 21 days cycle. One-way analysis of variance followed by LSD post hoc test was used for comparison of variables. P value <0.05 was considered to be significant. The comparison of the studied groups revealed that COCPs containing levonorgestrel plus ethinylestradiol resulted in significantly lower adiponectin level, and significantly higher leptin and resistin levels with more atherogenic lipid profile presented by significantly higher LDL-C, significantly lower HDL-C concentrations, and significantly higher atherogenic index. Formulation containing ethinylestradiol combined with gestodene neither altered adipose tissue function nor showed deleterious effect on lipid panel. Formulation containing ethinylestradiol combined with drospirenone resulted in significantly higher HDL-C and adiponectin concentrations. In conclusion, the uptake of COCPs containing levonorgestrel plus ethinylestradiol is associated with high cardiovascular risk since this formulation showed significantly lower adiponectin concentration, significantly higher leptin, resistin, and atherogenic index as compared to other studied groups. By contrast, the formulations containing ethinylestradiol combined with third generation progestin gestodene or fourth generation progestin drospirenone are associated with low cardiovascular risk since they neither altered adipose tissue function nor impaired lipoprotein metabolism as experienced by their favorable effect on leptin, adiponectin, and resistin, with non-changed atherogenic index, higher HDL-C levels and lower LDL-C levels as compared to levonorgestrel plus ethinylestradiol formulation.

Transplantation of periaortic adipose tissue from angiotensin receptor blocker-treated mice markedly ameliorates atherosclerosis development in apoE-/- mice.

Perivascular adipose tissue is implicated in vasoreactivity; however, its effect on atherosclerosis remains undefined. We examined the effect of a high-cholesterol diet (HCD) on phenotypic alterations of the thoracic periaortic adipose tissue (tPAT) in apoE-deficient (apoE(-/-)) mice. Gene expression of the components of the renin angiotensin system and that of macrophage markers were significantly higher in apoE(-/-) mice fed an HCD than in those fed a chow diet (CD). These changes were absent both in angiotensin II (AngII) receptor blocker (ARB)-treated apoE(-/-) mice and in Ang II type 1 (AT1) receptor-deficient apoE(-/-) (Agtr1(-/-)/apoE(-/-)) mice. To evaluate their effect on atherosclerosis, we transplanted tPAT into apoE(-/-) mice alongside the distal abdominal aorta. Transplanted tPAT was harvested from apoE(-/-) and Agtr1(-/-)/apoE(-/-) mice fed a CD (tPAT-CD/apoE(-/-), tPAT-CD/Agtr1(-/-)/apoE(-/-)), HCD (tPAT-HCD/apoE(-/-), tPAT-HCD/Agtr1(-/-)/apoE(-/-)), or HCD in combination with ARB treatment (tPAT-HCD/ARB/apoE(-/-)). Four weeks after transplantation, a significantly increased oil red O-positive area was observed in the aorta of tPAT-HCD/apoE(-/-) mice than in tPAT-CD/apoE(-/-) mice. Such a change was absent in tPAT-HCD/ARB/apoE(-/-) and tPAT-HCD/Agtr1(-/-)/apoE(-/-) mice. Our findings demonstrated that AT1 receptor plays a crucial role in HCD-induced phenotypic alterations of tPAT, modulation of which could exert beneficial effects on atherosclerosis.

Science is innate!

AbstractNo abstract.

Adipose phenotype predicts early human autogenous arteriovenous hemodialysis remodeling

Substantial proportions of autogenous arteriovenous fistulas (AVFs) for hemodialysis access fail to mature for unclear reasons. AVFs develop in a large mass of surrounding adipose tissue that is increasingly recognized as an active participant in the vascular response to injury via paracrine and endocrine mechanisms. We thus hypothesized that baseline phenotypic characteristics of the adipose tissue juxtaposed to the developing AVF associate with subsequent inward or outward vein wall remodeling. Clinical data and subcutaneous adipose tissue were collected from 22 consented patients undergoing AVF creation. Tissue was assayed (protein levels) for interleukin (IL)-6, IL-8, leptin, tumor necrosis factor-α, monocyte chemoattractant protein-1 (MCP-1), resistin, and adiponectin. Vein dimensions were acquired by duplex ultrasound imaging, preoperatively and at 4 to 6 weeks postoperatively, 1 cm cephalad to the arteriovenous anastomosis, which is the most common location of AVF stenosis). The vein at the assayed location outwardly remodeled 55.7% on average (median before, 3.7 mm; median after, 4.7 mm; P = .005). The preoperative vein diameter failed to correlate with postoperative size at the point of assay (R = 0.31; P = .155) unless two outliers were excluded (R = 0.64; P = .002). After removal of the same outliers, the correlation coefficient between venous diameter change (preoperative vs postoperative) and IL-8, tumor necrosis factor-α, MCP-1, resistin, and adiponectin was -0.49, -0.79, -0.66, -0.64, and -0.69, respectively (P < .05). Postoperative AVF flow volume correlated with MCP-1 (R = -0.53; P < .05) and adiponectin (R = -0.47; P < .05). These data reveal a novel relationship between local adipose phenotype and the eventual venous wall response to hemodynamic perturbation in humans. The predictive value of these mediators generally equaled or exceeded that of preoperative vein size. Beyond providing mechanistic insights into vascular wall adaptations due to flow perturbations, this discovery suggests that strategies focused on altering adipose tissue biology may improve AVF maturation.

B29 Two-point Magnitude Mri For Rapid Mapping Of Brown Adipose Tissue And Its Application To The R6/2 Mouse Model Of Huntingtons Disease

The recent discovery of active brown fat in human adults has led to renewed interest in the role of this key metabolic tissue in health and disease. This is particularly true for Huntington’s disease (HD), with a prominent energy deficit phenotype. HD patients show an unintended weight loss with normal or even high food intake already at early stages of the disease. Alterations in brown adipose tissue (BAT) including failure in thermogenesis are found in HD mouse models. Current methods for imaging BAT in vivo are in limited use because they are equipment-wise demanding and often prohibitively expensive. This prompted us to explore how a standard MRI set-up can be modified to visualise BAT in situ by taking advantage of its characteristic fat / water content ratio to differentiate it from surrounding white fat. We present a modified MRI protocol for use on an 11.7 T small animal MRI scanner to visualise and quantify BAT in wild-type and disease model laboratory mice. In this application study using the R6/2 transgenic mouse model of HD we demonstrate a significantly reduced BAT volume in HD mice vs. matched controls (n = 5 per group). This finding provides a plausible structural explanation for the previously described temperature phenotype of HD mice and underscores the significance of peripheral tissue pathology for the HD phenotype. On a more general level, the results demonstrate the feasibility of MR-based BAT imaging in rodents in vivo and open the path towards transferring this imaging approach to human patients. Future studies are needed to determine if this method can be used to track disease progression in HD and other disease entities associated with BAT abnormalities, including metabolic conditions such as obesity, cachexia, and diabetes. Funding EHDN seed fund 414.

A20 Adipose Tissue Alterations In Huntington's Disease

Traditionally, Huntington9s disease (HD) pathology has been considered to arise from degeneration of basal ganglia and cortex. However, the causative mutant huntingtin protein is expressed in cells and tissue throughout the body, and peripheral pathology is evident early in the disease. Changes in gene expression in brain as well as and peripheral tissues, have been shown in human HD as well as in HD mice. Despite weight loss, there is an enhanced accumulation of body fat in mid-life in several HD mouse models. This altered body composition has been shown to be accompanied by dysfunctional white adipocytes and defective brown adipose tissue thermogenesis. HD mouse white adipose tissue abnormalities have been shown to be progressive and to occur alongside impaired expression of mature adipocyte genes. We have now conducted a gene expression analysis of human adipose tissue and the results suggest alterated gene expression in fatty acid metabolism pathways, angiotensin signalling pathways and immune pathways in HD adipose tissue. Possibly, HD peripheral tissue studies, and adipose tissue investigations, could contributed to our understanding of molecular mechanisms through which mutant HTT leads to cell dysfunction and further, could be used to identify HD-related gene expression signatures.

Adipose tissue and metabolic alterations: regional differences in fat cell size and number matter, but differently: a cross-sectional study.

White adipose tissue can expand by increasing the size and/or number of fat cells. Although increased sc and visceral fat cell size associates with an adverse metabolic profile, the relationship with fat cell number in either depot is unknown. We hypothesized that adipocyte number and size displayed different relationships with clinically relevant metabolic variables. This was a cross-sectional study of 204 patients scheduled for gastric bypass surgery. Fat cell size and number were determined in visceral and abdominal sc adipose tissue and related to insulin sensitivity (by hyperinsulinemic euglycemic clamp), fasting plasma levels of insulin, triglycerides and high-density lipoprotein (HDL) cholesterol. Visceral and sc fat cell volumes were positively correlated with insulin and triglyceride levels and negatively with insulin sensitivity and HDL-cholesterol (P = .0020 or better). In contrast, although visceral fat cell number did not associate with any metabolic parameter, sc adipocyte number displayed a positive association with insulin sensitivity and HDL-cholesterol and a negative relationship with insulin and triglyceride levels (P = .0014 or better). All results were independent of body fat mass. Variations in fat cell size and number correlate differently with metabolic parameters in obesity. Increased fat cell size in visceral and sc depots associates with a pernicious metabolic profile, whereas increased sc, but not visceral, fat cell number correlates with a more beneficial phenotype. Whether determination of sc fat cell number, in addition to adipocyte size, may have a predictive value for the risk of type 2 diabetes needs to be demonstrated in prospective or mechanistic studies.

Capsaicin-induced transcriptional changes in hypothalamus and alterations in gut microbial count in high fat diet fed mice

Obesity is a global health problem and recently it has been seen as a growing concern for developing countries. Several bioactive dietary molecules have been associated with amelioration of obesity and associated complications and capsaicin is one among them. The present work is an attempt to understand and provide evidence for the novel mechanisms of anti-obesity activity of capsaicin in high fat diet (HFD)-fed mice. Swiss albino mice divided in three groups (n=8–10) i.e. control, HFD fed and capsaicin (2mg/kg, po)+HFD fed were administered respective treatment for 3months. After measuring phenotypic and serum related biochemical changes, effect of capsaicin on HFD-induced transcriptional changes in hypothalamus, white adipose tissue (WAT) (visceral and subcutaneous), brown adipose tissue (BAT) and gut microbial alterations was studied and quantified. Our results suggest that, in addition to its well-known effects, oral administration of capsaicin (a) modulates hypothalamic satiety associated genotype, (b) alters gut microbial composition, (c) induces “browning” genotype (BAT associated genes) in subcutaneous WAT and (d) increases expression of thermogenesis and mitochondrial biogenesis genes in BAT. The present study provides evidence for novel and interesting mechanisms to explain the anti-obesity effect of capsaicin.

Tadalafil ameliorates metabolic syndrome-induced alterations in visceral adipose tissue and liver: an experimental study in the rabbit

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Metabolic adaptations in skeletal muscle, adipose tissue, and whole-body oxidative capacity in response to resistance training

The effects of resistance training on mitochondrial biogenesis and oxidative capacity in skeletal muscle are not fully characterized, and even less is known about alterations in adipose tissue. We aimed to investigate adaptations in oxidative metabolism in skeletal muscle and adipose tissue after 8weeks of heavy resistance training in apparently healthy young men. Expression of genes linked to oxidative metabolism in the skeletal muscle and adipose tissue was assessed before and after the training program. Body composition, peak oxygen uptake (VO2 peak), fat oxidation, activity of mitochondrial enzyme in muscle, and serum adiponectin levels were also determined before and after resistance training. In muscle, the expression of the genes AdipoR1 and COX4 increased after resistance training (9 and 13%, respectively), whereas the expression levels of the genes PGC-1α, SIRT1, TFAM, CPT1b, and FNDC5 did not change. In adipose tissue, the expression of the genes SIRT1 and CPT1b decreased after training (20 and 23%, respectively). There was an increase in lean mass (from 59.7±6.1 to 61.9±6.2kg), VO2 peak (from 49.7±5.5 to 56.3±5.0ml/kg/min), and fat oxidation (from 6.8±2.1 to 9.1±2.7mg/kg fat-free mass/min) after training, whereas serum adiponectin levels decreased significantly and enzyme activity of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase did not change. Despite significant increases in VO2 peak, fat oxidation, and lean mass following resistance training, the total effect on gene expression and enzyme activity linked to oxidative metabolism was moderate.

Eicosapentaenoic acid reduces high‐fat diet‐induced insulin resistance by altering adipose tissue glycolytic and inflammatory function (383.8)

We previously reported Eicosapentaenoic Acid (EPA)'s ability to prevent high‐fat (HF) diet‐induced obesity, insulin resistance, and inflammation. In this study, we dissected mechanisms mediating anti‐inflammatory and anti‐lipogenic actions of EPA, using histology/ immunohistochemistry, transcriptomic and energetic analyses of adipose tissues from HF and HF‐EPA fed mice, or 3T3‐L1 adipocytes treated with or without EPA. Microarray and real time PCR analyses of adipose tissue from these mice showed that EPA decreased expression of genes associated with cell proliferation, apoptosis, adipogenesis and glucose metabolism (namely Fasn, Srebf1, Cebpa, Ncoa2, and Axin1). Preliminary extracellular flux studies indicate changes in glycolysis in differentiated 3T3‐L1 adipocytes treated with EPA, compared to those treated with palmitic acid (PA) alone or with EPA. These results are consistent with increased fatty acid oxidation‐related metabolites in gonadal fat after EPA supplementation. Histology and immunohistochemistry results showed a significantly lower mean adipocyte size and macrophage infiltration in mice fed a HF‐EPA diet vs. HF, indicating that EPA prevented HF‐diet induced adipocyte inflammation and hypertrophy. In conclusion, our studies demonstrate that EPA ameliorates glucose homeostasis at least in part by reducing adipose tissue inflammation, glycolysis and lipid accumulation.Grant Funding Source: USDA, AHA and TTU (COHS and OVPR)

Adipose dysfunction with aging is associated with resistance artery endothelial dysfunction and impaired angiogenic capacity (688.3)

Although tissue dysfunction is reported in aging, effects of aging on adipose tissue per se are not well studied. To address this, we assessed metabolic homeostasis, adipose tissue structure‐function and adipose artery endothelial function from young (6 mo) and old (29 mo) male B6D2F1 mice. Fasted blood glucose was not different with age but plasma insulin, homeostatic model assessment (HOMA‐) of insulin resistance (IR), and beta cell function (‐B) were increased by 84%, 54%, 57% respectively (P&lt;0.05) in old mice. Old mice also were glucose intolerant (P&lt;0.05), concomitant with increased plasma free fatty acids (P&lt;0.05) and liver triglycerides (P&lt;0.05). Despite no difference in body mass, epididymal white adipose tissue (eWAT) mass was 40% lower in old mice. There was ~60% reduction in mean adipocyte area (p&lt;0.01), 7‐fold increase in fibrosis (p&lt;0.01) and ~50% reduction in vascular density (p&lt;0.01) in old eWAT. There also was a 2‐fold reduction in in vitro eWAT angiogenesis and a ~25% reduction in endothelium dependent dilation to acetylcholine in eWAT arteries (p&lt;0.01) from old mice, without a reduction in endothelium independent dilation. Thus, aging results in metabolic dysfunction associated with increased circulating and ectopic lipids, altered adipose tissue morphology and reduced vascular density, concomitant with impaired angiogenic potential and endothelial dysfunction in adipose arteries.Grant Funding Source: Supported by R21 AG033755, K01 AG033196, R01 AG040297

Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity. Also, metformin treatment caused a significant decrease in liver weight, but not adiposity. As indicated by histological changes, metformin treatment decreased hepatic steatosis, but not the size of adipocytes. In addition, metformin treatment caused an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK), which was accompanied by an increase in the phosphorylation of liver acetyl-CoA carboxylase and decreases in the phosphorylation of liver c-Jun N-terminal kinase 1 (JNK1) and in the mRNA levels of lipogenic enzymes and proinflammatory cytokines. However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In cultured hepatocytes, metformin treatment increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. Additionally, in bone marrow-derived macrophages, metformin treatment partially blunted the effects of lipopolysaccharide on inducing the phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65 and on increasing the mRNA levels of proinflammatory cytokines. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages.

Adipocytes in Skin Health and Disease

Adipocytes are intimately associated with the dermal compartment of the skin, existing in a specialized dermal depot and displaying dynamic changes in size during tissue homeostasis. However, the roles of adipocytes in cutaneous biology and disease are not well understood. Traditionally, adipocytes within tissues were thought to act as reservoirs of energy, as thermal, or as structural support. In this review, we discuss recent studies revealing the cellular basis of the dynamic development and regenerative capacity of dermal adipocytes associated with the hair cycle and following injury. We discuss and speculate on potential roles of dermal adipocytes in cutaneous biology with an emphasis on communication during hair follicle growth and wound healing. Finally, we explore how alterations in the dermal adipose tissue may support clinical manifestations of cutaneous diseases such as lipodystrophy, obesity, and alopecia.

Introduction to the Jubilee issue in Endocrine Pathology

Endocrine Pathology is 25 years old! In celebration of this anniversary, the editors, editorial board, and the publisher have solicited articles from leading endocrine pathologists in various aspects of the endocrine system. These articles review the developments and accomplishments within endocrine pathology over the past quarter century. Introductory articles on the history of the Journal and its sponsoring organization, the Endocrine Pathology Society, are provided by doctors Kovacs and Asa and DeLellis. Following these are reviews covering pituitary, thyroid (follicular as well as C cell lesions), parathyroid, ovary, gastrointestinal endocrine cells, pancreatic islets, and adrenal (both cortex and medulla). We are please to also include articles on alterations in adipose tissue and their relationship to glucose metabolism. The articles cover aspects of endocrine pathology known 25 years ago and trace the exciting developments in the understanding of pathophysiology and molecular alterations in the major endocrine glands. In all of pathology over the past quarter century, only the knowledge explosion in hematopathology can compare to that seen in endocrinology andmetabolism. Our expert authors have, in many cases, been at the forefront and in the research laboratories that have been responsible for the acquisition of this new knowledge. We present this issue to the readership of the Journal with the hope that they will recognize the important contributions that have been made in this field and the value that these have given to clinical medicine and the care of patients. We anticipate that at the Golden Jubillee of the Journal, the knowledge in this field will have quadrupled and that our understanding of molecular biology, proteomics, metabolomics, nanotechnology, and explorations in fields as yet unknown will enhance developments in research and clinical techniques to help patients in the future. Virginia A. LiVolsi, MD Anne Marie McNicol, MD