Seasonal Regulation of Metabolism: The Effect of Wintertime Fasting and Autumnal Fattening on Key Central Regulators of Metabolism and the Metabolic Profile of the Raccoon Dog (Nyctereutes Procyonoides).

Investigations into the mechanisms regulating obesity are frantic and novel translational approaches are needed. The raccoon dog (Nyctereutes procyonoides) is a canid species representing a promising model to study metabolic regulation in a species undergoing cycles of seasonal obesity and fasting. To understand the molecular mechanisms of metabolic regulation in seasonal adaptation, we analyzed key central nervous system and peripheral signals regulating food intake and metabolism from raccoon dogs after autumnal fattening and winter fasting. Expressions of neuropeptide Y (NPY), orexin-2 receptor (OX2R), pro-opiomelanocortin (POMC) and leptin receptor (ObRb) were analyzed as examples of orexigenic and anorexigenic signals using qRT-PCR from raccoon dog hypothalamus samples. Plasma metabolic profiles were measured with 1H NMR-spectroscopy and LC-MS. Circulating hormones and cytokines were determined with canine specific antibody assays. Surprisingly, NPY and POMC were not affected by the winter fasting nor autumn fattening and the metabolic profiles showed a remarkable equilibrium, indicating conserved homeostasis. However, OX2R and ObRb expression changes suggested seasonal regulation. Circulating cytokine levels were not increased, demonstrating that the autumn fattening did not induce subacute inflammation. Thus, the raccoon dog developed seasonal regulatory mechanisms to accommodate the autumnal fattening and prolonged fasting making the species unique in coping with the extreme environmental challenges.

Angiopoietin-1 protects 3T3-L1 preadipocytes from saturated fatty acid-induced cell death.

Cross talk between endothelial cells and adipocytes is vital to adipocyte functions, but little is known about the mechanisms or factors controlling the process. Angiogenesis is a critical component linking the endothelium to healthy adipogenesis, yet it is not known if or how it is involved in adipocyte physiology. Therefore, the purpose of this study was to determine the effect of angiopoietin-1 (Ang-1) and -2 (Ang-2) as well as their receptor, Tie-2, on adipocyte physiology. 3T3-L1 pre- and mature adipocytes were found to express Ang-1, Ang-2, and Tie-2, which decrease upon polyunsaturated fatty acid treatment. Furthermore, 3T3-L1 cells treated with recombinant Ang-1 or Ang-2 increased expression of the antiapoptotic gene Bcl-x and decreased expression of the proapoptotic gene Casp-8. Next, preadipocytes were treated with saturated fatty acids (SFAs) to induce cell stress. SFA-mediated splicing of X-box-binding protein-1 was reduced by co-treatment with Ang-1, and cell viability was improved in the presence of SFAs + Ang-1. Taken together, these results indicate that Ang-1 may protect preadipocytes from SFA-induced apoptosis and endoplasmic reticulum stress.

Stromal vascular fraction-enriched platelet-rich plasma therapy reverses the effects of androgenetic alopecia.

BACKGROUND: Since antiquity, humans have been trying to devise remedies to cure androgenetic alopecia (AGA). These efforts include use of oral and topical concoctions and hair transplant strategies. As AGA affects people of all colors and creed, there has been a continuous effort to find a magic bullet against AGA. Unfortunately, to date, all the strategies to negate AGA effects have limitations and thus require new treatment options. AIM: To evaluate the efficacy of use of stromal vascular fraction (SVF) in androgenetic alopecia patients. METHODS: Stromal vascular fraction was obtained by enzymatic digestion of autologous adipose tissue. The patients were divided into two groups, that is, platelet-rich plasma (PRP) group and SVF-PRP group. In PRP group, only PRP was injected, while in SVF-PRP group a mixture of PRP and SVF was injected in affected scalp areas. After two sessions (4 weeks apart), the patients in both groups were assessed and analyzed using various parameters. RESULTS: Mean hair density in PRP group was increased from 52.44 hair/cm2 to 63.72 hair/cm2 (21.51% increase); while in SVF-PRP group, it was 37.66 hair/cm2 before treatment and 57.11 hair/cm2 after SVF-PRP therapy (51.64% increase). Percentage reduction in pull test was more significant in SVF-PRP group (80.78 ± 5.84) as compared to PRP group (34.01 ± 22.44). The physician and patient assessment scores also indicated a significant improvement in SVF-PRP group. CONCLUSION: A combined SVF-PRP therapy reversed effects of AGA more efficiently as compared to PRP therapy alone.

Lysimachia Capillipes Inhibit Adipogenesis via Angiogenesis Inhibition.

Obesity is a common and increasingly prevalent human condition due to unhealthy diet and less-exercise lifestyle. Development of obesity is associated with substantial modulation of adipose tissue structure. The expansion of adipose tissue is linked to the development of its vasculature, and modulation of angiogenesis may have the potential to impair adipose tissue development. In this study, we used obesity model of zebrafish fed by egg yolk to investigate the effect of Lysimachia capillipes on the obesity. The results showed that Lysimachia capillipes inhibited angiogenesis of adipose tissue in transgenic zebrafish Tg (Fli 1: EGFP), which was similar to surppressing effect of TNP-470, which was accompanied by decreased Oil Red O staining of the zebrafish. The treatment of Lysimachia capillipes reduced expression of MTP significantly, but modestly reduced expression of Ppar g, FABP10a, and CD36 level through ISH, which was accordant with the results by PCR analysis. The study proved that Lysimachia capillipes might possess novel therapeutic properties for prevention and treatment of obesity.

Photobiomodulation (PBM) promotes angiogenesis in-vitro and in chick embryo chorioallantoic membrane model.

The application of light in various therapeutic settings known as Photobiomodulation (PBM) is well established. Indications are the improvement of wound healing and tissue regeneration, scarring, and perfusion as well as pain therapy. Tissue perfusion is mandatory for successful wound healing. Nevertheless, there is a lack of mechanistic studies. We investigate the potential effect of PBM from light emitting diodes (LED) at 635 nm, 80 mW/cm2, 24 J/cm2 on angiogenesis in a two-part study: 1.) Investigation of the effect of PBM on the proliferation of endothelial cells and on vasculogenesis in a co-culture model of endothelial cells and stem cells. 2.) Investigation of the influence of PBM at chick egg chorioallantoic membrane (CAM) assays with fresh human skin xenografts. In both study phases, we observed a stimulating effect of PBM at 635 nm; in part 1: for proliferation of HUVEC (human umbilical vein endothelial cells) (25833 ± 12859 versus 63002 ± 35760 cells/well, p < 0.05, for cellular network formation (2.1 ± 2.1 versus 4.6 ± 3.5, p < 0.05) and for less cell compactness p = 0.01; in part 2: for the increase of number of vessel junctions per ROI (region of interest) (15.9 ± 2.6 versus 20.8 ± 5.4, p < 0.05). Our results suggest significant promotion of angiogenesis by PBM at 635 nm in vitro and in vivo.

Comparative Efficacy of Autologous Stromal Vascular Fraction and Autologous Adipose-Derived Mesenchymal Stem Cells Combined With Hyaluronic Acid for the Treatment of Sheep Osteoarthritis.

The current study explored whether intra-articular (IA) injection of autologous adipose mesenchymal stem cells (ASCs) combined with hyaluronic acid (HA) achieved better therapeutic efficacy than autologous stromal vascular fraction (SVF) combined with HA to prevent osteoarthritis (OA) progression and determined how long autologous ASCs combined with HA must remain in the joint to observe efficacy. OA models were established by performing anterior cruciate ligament transection (ACLT) and medial meniscectomy (MM). Autologous SVF (1×107 mononuclear cells), autologous low-dose ASCs (1×107), and autologous high-dose ASCs (5×107) combined with HA, and HA alone, or saline alone were injected into the OA model animals at 12 and 15 weeks after surgery, respectively. Compared with SVF+HA treatment, low-dose ASC+HA treatment yielded better magnetic resonance imaging (MRI) scores and macroscopic results, while the cartilage thickness of the tibial plateau did not differ between low, high ASC+HA and SVF+HA treatments detected by micro-computed tomography (µCT). Immunohistochemistry revealed that high-dose ASC+HA treatment rescued hypertrophic chondrocytes expressing collagen X in the deep area of articular cartilage. Western blotting analysis indicated the high- and low-dose ASC+HA groups expressed more collagen X than did the SVF+HA group. Enzyme-linked immunosorbent assay showed treatment with both ASC+HA and SVF+HA resulted in differing anti-inflammatory and trophic effects. Moreover, superparamagnetic iron oxide particle (SPIO)-labeled autologous ASC signals were detected by MRI at 2 and 18 weeks post-injection and were found in the lateral meniscus at 2 weeks and in the marrow cavity of the femoral condyle at 18 weeks post-injection. Thus, IA injection of autologous ASC+HA may demonstrate better efficacy than autologous SVF+HA in blocking OA progression and promoting cartilage regeneration, and autologous ASCs (5×107 cells) combined with HA potentially survive for at least 18 weeks after IA injection.

Inferior In Vivo Osteogenesis and Superior Angiogenesis of Human Adipose­Derived Stem Cells Compared with Bone Marrow­Derived Stem Cells Cultured in Xeno­Free Conditions.

The possibility of using adipose tissue-derived stromal cells (ATSC) as alternatives to bone marrow-derived stromal cells (BMSC) for bone repair has garnered interest due to the accessibility, high cell yield, and rapid in vitro expansion of ATSC. For clinical relevance, their bone forming potential in comparison to BMSC must be proven. Distinct differences between ATSC and BMSC have been observed in vitro and comparison of osteogenic potential in vivo is not clear to date. The aim of the current study was to compare the osteogenesis of human xenofree-expanded ATSC and BMSC in vitro and in an ectopic nude mouse model of bone formation. Human MSC were implanted with biphasic calcium phosphate biomaterials in subcutis pockets for 8 weeks. Implant groups were: BMSC, ATSC, BMSC and ATSC mixed together in different ratios, as well as MSC primed with either osteogenic supplements (250 µM ascorbic acid, 10 mM ß-glycerolphosphate, and 10 nM dexamethasone) or 50 ng/ml recombinant bone morphogenetic protein 4 prior to implantation. In vitro results show osteogenic gene expression and differentiation potentials of ATSC. Despite this, ATSC failed to form ectopic bone in vivo, in stark contrast to BMSC, although osteogenic priming did impart minor osteogenesis to ATSC. Neovascularization was enhanced by ATSC compared with BMSC; however, less ATSC engrafted into the implant compared with BMSC. Therefore, in the content of bone regeneration, the advantages of ATSC over BMSC including enhanced angiogenesis, may be negated by their lack of osteogenesis and prerequisite for osteogenic differentiation prior to transplantation. Stem Cells Translational Medicine 2017;6:2160-2172.

Reduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis.

It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet-induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors.

Pharmacokinetic pilot study of the antiangiogenic activity of standardized platycodi radix.

INTRODUCTION: Platycodi radix is a radish used in food, such as Korean kimchi, and has been shown to cause weight loss in rodents. Platycodin D is considered its active ingredient and has been shown to inhibit lipases. The authors hypothesized that platycodi radix and the platycodin D it contains inhibit angiogenesis; another mechanism for weight loss. METHODS: This study tested platycodi radix extract, platycodin D, and an extract of platycodi radix standardized to platycodin D for their ability to inhibit angiogenesis in a human adipose tissue assay. This study treated five healthy volunteers, orally, with platycodi radix extract standardized to 414 mg of platycodin D. Three volunteers were treated under fasting conditions, one volunteer with a 400 kcal meal, and one volunteer treated with a placebo. Blood was drawn over 5 hours to compare serum inhibition of the human adipose tissue angiogenesis. RESULTS: Platycodin radix extract, platycodin D, and platycodi radix extract standardized to platycodin D all inhibited angiogenesis. The three volunteers who consumed platycodi radix extract standardized to 414 mg of platycodin D had a 25.76% reduction in angiogenesis from baseline at 60 minutes (P<0.002), and had a statistically significant reduction in angiogenesis from 30 to 240 minutes (P<0.05 to P<0.002). The placebo decreased angiogenesis by 5.6% between 30 and 240 minutes, compared with 17.8% by the extract. The meal delayed absorption by approximately 3.5 hours. CONCLUSION: Platycodi radix extract standardized to platycodin D inhibited angiogenesis in human volunteers, and paves the way for a dose-response study and a human clinical obesity trial.

Cosmeceuticals for cellulite.

Cellulite is characterized by alterations to the skin surface, presenting as dimpled or puckered skin of the buttocks and posterior and lateral thighs. It mainly affects women. Cellulite occurrence is believed to be due to structural, inflammatory, morphological and biochemical alterations of the subcutaneous tissue. However, its pathogenesis is not completely understood. Topical treatments for cellulite include many agents, such those that increase the microcirculation flow, agents that reduce lipogenesis and promote lipolysis, agents that restore the normal structure of dermis and subcutaneous tissue, and agents that scavenge free radicals or prevent their formation. There are many cosmetic and medical treatments for cellulite. However, there is little clinical evidence of an improvement in cellulite, and none have been shown to lead to its resolution. The successful treatment of cellulite will ultimately depend upon our understanding of the physiopathology of cellulite adipose tissue.

Impact of a mechanical massage on gene expression profile and lipid mobilization in female gluteofemoral adipose tissue.

BACKGROUND: Gluteofemoral adipose tissue areas are known to be poorly metabolically reactive. Mechanical massage has previously been reported to show morphological and functional impact on this tissue. The present study was carried out to delve more deeply into the mechanistic considerations regarding the incidence of a mechanical massage technique on gene expression profile and ß-adrenergic-mediated lipid mobilization in female femoral adipose tissue. METHODS: Twelve premenopausal healthy women were included and received 12 sessions of calibrated mechanical massage (Endermologie®). Total RNA was extracted from femoral adipose tissue biopsies for gene expression studies. Microdialysis was carried out in the femoral adipose tissue in order to assess lipolytic responsiveness (via glycerol determination) and changes in local blood flow following perfusion of a lipolytic agent, isoproterenol. Evaluations were performed before and after the 6-week experimental period. RESULTS: Mechanical massage initiated important modifications in gene expression profile. The lipid-mobilizing effect of isoproterenol was enhanced after the experimental period. Basal local blood flow and isoproterenol-induced vasodilatation were also improved. CONCLUSION: The protocol of mechanical massage used in the study promoted noticeable changes in the expression of genes involved in metabolic pathways. The lipolytic and local adipose tissue blood flow responses initiated by isoproterenol were significantly enhanced.

The anti-angiogenic herbal extracts Ob-X from Morus alba, Melissa officinalis, and Artemisia capillaris suppresses adipogenesis in 3T3-L1 adipocytes.

CONTEXT: Growing adipose tissue is thought to require adipogenesis, angiogenesis, and extracellular matrix (ECM) remodeling. Close examination of developing adipose tissue microvasculature reveals that angiogenesis often precedes adipogenesis. Since our previous study demonstrated that Ob-X, the anti-angiogenic herbal composition composed of Melissa officinalis L. (Labiatae), Morus alba L. (Moraceae), and Artemisia capillaris Thunb. (Compositae), reduced adipose tissue mass in obese mice, we hypothesized that adipogenesis can be inhibited by Ob-X. OBJECTIVE: To investigate the effects of the anti-angiogenic herbal extracts Ob-X on adipogenesis in 3T3-L1 adipocytes. MATERIALS AND METHODS: After differentiated 3T3-L1 adipocytes were treated with Ob-X, we studied the effects of Ob-X on triglyceride accumulation and expression of genes involved in adipogenesis, angiogenesis, and ECM remodeling. RESULTS: Treatment of cells with Ob-X inhibited lipid accumulation and adipocyte-specific gene expression caused by troglitazone or monocyte differentiation-inducing (MDI) mix. Ob-X reduced mRNA levels of angiogenic factors (vascular endothelial growth factor-A, -B, -C, -D, and fibroblast growth factor-2) and matrix metalloproteinases (MMPs; MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenic inhibitors [(thrombospondin-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2)] in differentiated cells. MMP-2 and MMP-9 activities were also decreased in Ob-X-treated cells. DISCUSSION AND CONCLUSION: These results suggest that the anti-angiogenic herbal composition Ob-X inhibits differentiation of preadipocytes into adipocytes. These events may be mediated by changes in the expression of genes involved in lipogenesis, angiogenesis, and the MMP system. Thus, by reducing adipogenesis, anti-angiogenic Ob-X provides a possible therapeutic approach for the prevention and treatment of human obesity and its related disorders.

The anti-angiogenic herbal composition Ob-X inhibits adipose tissue growth in obese mice.

OBJECTIVE: The growth and development of adipose tissue are thought to be associated with angiogenesis and extracellular matrix remodeling. As the composition of the herbal extract called Ob-X has been shown to have both anti-angiogenic and matrix metalloproteinase (MMP)-inhibiting activities, we hypothesized that growth of adipose tissue can be regulated by Ob-X. MATERIALS AND METHODS: The effects of Ob-X on angiogenesis and extracellular matrix remodeling were measured using in vitro and ex vivo assays. The effects of Ob-X on adipose tissue growth were investigated in nutritionally obese mice. RESULTS: Ob-X inhibited angiogenesis in a dose-dependent manner in the human umbilical vein endothelial cell tube formation assay in vitro and the rat aortic ring assay ex vivo. Ob-X also suppressed MMP activity in vitro. Administration of Ob-X to high fat diet-induced obese mice produced significant reductions in body weight gain and adipose tissue mass compared with control. The mass of both visceral (VSC) and subcutaneous (SC) fat was reduced in Ob-X-treated mice. The size of adipocytes in VSC and SC adipose tissues was also significantly reduced in Ob-X-treated mice. Ob-X treatment decreased the blood vessel density and MMP activity in VSC adipose tissues of nutritionally obese mice. Ob-X reduced mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1 and TIMP-2) in SC and VSC adipose tissues of nutritionally obese mice. CONCLUSION: Ob-X, which has anti-angiogenic and MMP-inhibitory activities, reduces adipose tissue mass in nutritionally induced obese mice, providing evidence that adipose tissue growth and development may be prevented by inhibiting angiogenesis. In addition, these data suggest that regulation of adipose tissue growth by inhibiting angiogenesis may alter the expression of genes involved in angiogenesis and the MMP system.

Fumagillin reduces adipose tissue formation in murine models of nutritionally induced obesity.

The effect of fumagillin (a methionine aminopeptidase-type 2 (Met-AP2) inhibitor, with antiangiogenic properties) was investigated in murine models of diet-induced obesity. Eleven-week-old male C57Bl/6 mice (group 1) were given fumagillin by oral gavage at a dose of 1 mg/kg/day during 4 weeks while fed a high-fat diet (HFD) (20.1 kJ/g), and control mice (group 2) received solvent and were pair-fed. At the end of the experiment, body weights in group 1 were significantly lower as compared to group 2 (P < 0.0005). The subcutaneous (SC) and gonadal (GON) fat mass was also significantly lower in group 1 (P < 0.005 and P < 0.05, respectively). Adipocytes were smaller in adipose tissues of mice in group 1, associated with higher adipocyte density. Blood vessel density normalized to adipocyte density was lower in group 1 adipose tissues. However, in mice with established obesity monitored to maintain the same body weight and fat mass as controls, short-term fumagillin administration was also associated with adipocyte hypotrophy (P = 0.01) without affecting blood vessel size or density. Thus, treatment with fumagillin impaired diet-induced obesity in mice, associated with adipocyte hypotrophy but without marked effect on adipose tissue angiogenesis.

Peptide designed to elicit apoptosis in adipose tissue endothelium reduces food intake and body weight.

OBJECTIVE: Because adipose tissue is highly vascularized, modifying adipose tissue vasculature may provide a novel method for reducing body fat. A peptide sequence that elicits apoptosis of endothelium in white fat potently reduced body weight. We sought to determine how inhibiting adipose tissue vasculature changes key aspects of energy balance regulation and the neuroendocrine system that maintains energy balance. RESEARCH DESIGN AND METHODS: Lean and obese mice or rats were treated with proapoptotic peptide for 4 or 27 days. Daily energy intake and expenditure were measured in mice on a low- (LFD) or high-fat diet (HFD) and in rats on a HFD. A conditioned taste aversion test was performed to assess whether proapoptotic peptide produces visceral illness. Hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocoritin (POMC) mRNA expression and plasma leptin levels were evaluated. RESULTS: Proapoptotic peptide completely reversed HFD-induced obesity in mice and reduced body weight in mice and rats on a HFD but not in those on a LFD. Fat loss occurred with no change of energy expenditure but reduced food intake that occurred without signs of illness and despite reduced circulating leptin and reduced hypothalamic POMC gene expression, indicating that the decrease in food intake is independent of the action of leptin. CONCLUSIONS: These experiments provide compelling evidence for a previously unknown relationship between the status of adipose tissue vasculature and the regulation of food intake.

Use of the microdialysis technique to assess lipolytic responsiveness of femoral adipose tissue after 12 sessions of mechanical massage technique.

BACKGROUND: Adipocytes in femoral areas are known to be metabolically 'silent'. Changes related to fat cell hypertrophy may be involved in the formation of cellulite. A mechanical massage technique, with circulatory and dermotrophic properties, has been shown to have an impact on clinical evaluations (i.e. changes in morphometric measurements) in cellulite areas. Whether this technique affected lipolytic responsiveness in subcutaneous adipose tissue of cellulite areas was not known. OBJECTIVE: Using a microdialysis technique in subcutaneous adipose tissue, a study was carried out to test the in situ incidence of a mechanical massage technique in terms of adipose tissue responsiveness to a lipolytic challenge. MATERIALS AND METHODS: Nine healthy women volunteers with cellulite (grade > or = 2) were included and treated with 12 sessions of mechanical massage technique (Endermologie). Microdialysis has been carried out in the femoral adipose tissue in order to assess lipolytic responsiveness via glycerol determination following perfusion of a lipolytic agent (0.1, 1 and 10 microm isoproterenol). Clinical evaluations (measurements of waist, thighs and skin fold) were carried out in parallel. All evaluations were performed before and after treatment. RESULTS: The studied intervention lowered resting dialysate glycerol levels in femoral adipose tissue. The lipid-mobilizing effect of isoproterenol was enhanced after 1 month of treatment. In addition, a clear decrease of morphometric measurements (mean decrease on thighs perimeter: 3.1 to 3.3 cm, P < 0.01) was observed. CONCLUSION: These results suggest an increase in the lipolytic responsiveness of femoral adipose tissue in women with cellulite having undergone 12 sessions of mechanical massage.

The potential of adiponectin in driving arthritis.

Articular adipose tissue is a ubiquitous component of human joints, but its local functions are largely unknown. Because recent studies revealed several links between adipose tissue, adipocytokines, and arthritis, we investigated the expression of the adipocytokine adiponectin and its functional role in articular adipose tissue and synovium of patients with different arthritides. In contrast to its protective role in endocrinological and vascular diseases, adiponectin was found to be involved in key pathways of inflammation and matrix degradation in the human joint. The effects of adiponectin in human synovial fibroblasts appear to be highly selective by inducing only two of the main mediators of rheumatoid arthritis pathophysiology, IL-6 and matrix metalloproteinase-1, via the p38 MAPK pathway. Owing to the observation that these effects could be inhibited by different TNF-alpha inhibitors, adipocytokines such as adiponectin may also be key targets for therapeutic strategies in inflammatory joint diseases. In summary, articular adipose tissue and adipocytokines cannot be regarded as innocent bystanders any more in chronic inflammatory diseases such as arthritis.

Morphology of ferret subcutaneous adipose tissue after 6-month daily supplementation with oral beta-carotene.

Adipose tissue is an important retinoid depot and retinoids are known to influence white and brown adipocyte metabolism. Identifying nutrients that can affect the biological activity of the adipose organ would be of great medical interest in the light of the current obesity epidemic and related disorders in developed countries. The vast majority of mammal studies of chronic administration of oral beta-carotene have used murine models, while few have employed mammals exhibiting uptake and processing of intestinal beta-carotene similar to those of humans. While rodents transform practically all ingested beta-carotene into retinol, in ferrets, as in humans, part of the beta-carotene is absorbed and released into the circulation intact. We studied the effects of 6-month daily administration of two doses of oral beta-carotene (0.8 or 3.2 mg/kg/day) on ferret body weight, size of body fat depots, and, using morphological and morphometric methods, on subcutaneous (inguinal) white adipose tissue (WAT). Because of the oral mode of administration, liver, stomach, and small and large intestine were also studied. Control animals received the vehicle. Data show that at the end of treatment the higher dose induced significantly higher body weight compared with controls and significantly higher inguinal fat depot compared with animals treated with the lower dose. In addition, chronic treatment with beta-carotene induced a dose-dependent hypertrophy of white adipocytes and increased neoangiogenesis in subcutaneous WAT in all treated ferrets. Vasculogenesis was independent of adipocyte hypertrophy. We also found focally evident liver steatosis in the ferrets treated with the higher dose of beta-carotene. The other gastrointestinal tract organs studied were not significantly different from those of control animals.