Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8–36.2 years of age, who were discordant (ΔBMI >3 kg/m2, mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m2, n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage.

Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO,PGE2, IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway c-JunNH2-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, andPGE2, and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, andPGE2production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.

Abstract:  Traditional non‐steroidal anti‐inflammatory drugs (NSAID) and selective cyclooxygenase‐2 (COX‐2) inhibitors are widely used in the treatment of pain, including bone fracture pain and orthopaedic post‐operative pain. The gastrointestinal and cardiovascular adverse effects of NSAIDs are acknowledged, but their effects on bone are less widely known. Prostaglandins play an important role in the regulation of osteoblast and osteoclast functions, and inhibition of prostaglandin production retards bone formation. Therefore, NSAIDs could be expected to have significant consequences in divergent clinical situations where bone formation or remodelling is a contributing factor. The present survey reviews current experimental and clinical evidence related to two of those conditions (i.e. on ectopic bone formation and on bone fracture healing). NSAIDs are used clinically to prevent ectopic bone formation (also known as heterotopic ossification) (e.g. after total hip arthroplasty or trauma). The efficacy of NSAIDs in the avoidance of heterotopic ossification has been documented in controlled clinical trials, but the inherent risks (e.g. on healing processes and on loosening of prostheses) need further studies. At the same time, NSAIDs are widely used in the treatment of fracture pain, and their inhibitory effects on the ongoing bone healing process have raised concerns. Results of fracture healing studies in animals treated with NSAIDs or in mice lacking COX‐2 gene show that inhibition or deficiency of COX‐2 impairs the bone healing process. The limited clinical data also support the assumption that inhibition of COX‐2 by non‐selective or COX‐2‐selective NSAIDs delays fracture healing. However, the clinical significance of the effect in various patient groups needs to be carefully assessed and further investigations are needed to characterize the patients at the highest risk for NSAID‐induced delayed fracture healing and its complications. In the meantime, use of NSAIDs in fracture patients should be cautious, keeping in mind the benefits of pain relief and inhibition of ectopic bone formation on one hand, and the risks of non‐union and retarded union on the other hand.

Introduction: Adiponectin is an adipokine that regulates energy metabolism and insulin sensitivity, but recent studies have pointed also to a role in inflammation and arthritis. The purpose of the present study was to investigate the association and effects of adiponectin on inflammation and cartilage destruction in osteoarthritis (OA). Methods: Cartilage and blood samples were collected from 35 male OA patients undergoing total knee replacement surgery. Preoperative radiographs were evaluated using Ahlbäck classification criteria for knee OA. Circulating concentrations of adiponectin and biomarkers of OA, that is, cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase 3 (MMP-3), were measured. Cartilage samples obtained at the time of surgery were cultured ex vivo, and the levels of adiponectin, nitric oxide (NO), IL-6, MMP-1 and MMP-3 were determined in the culture media. In addition, the effects of adiponectin on the production of NO, IL-6, MMP-1 and MMP-3 were studied in cartilage and in primary chondrocyte cultures. Results: Plasma adiponectin levels and adiponectin released from OA cartilage were higher in patients with the radiologically most severe OA (Ahlbäck grades 4 and 5) than in patients with less severe disease (Ahlbäck grades 1 to 3). Plasma adiponectin concentrations correlated positively with biomarkers of OA, that is, COMP (r = 0.55, P = 0.001) and MMP-3 (r = 0.34, P = 0.046). Adiponectin was released by OA cartilage ex vivo, and it correlated positively with production of NO (r = 0.43, P = 0.012), IL-6 (r = 0.42, P = 0.018) and MMP-3 (r = 0.34, P = 0.051). Furthermore, adiponectin enhanced production of NO, IL-6, MMP-1 and MMP-3 in OA cartilage and in primary chondrocytes in vitro in a mitogen-activated protein kinase (MAPK)-dependent manner. Conclusions: The findings of this study show that adiponectin is associated with, and possibly mediates, cartilage destruction in OA.

Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear. We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3–10 kg m⁻², n=15) and concordant (ΔBMI 0–2 kg m⁻², n=5) young adult (22–35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A). The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91–0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6±0.9 kg m⁻²) had significantly larger adipocytes (volume 547±59 pl), than the lean co-twins (24.9±0.9 kg m⁻²; 356±34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death. Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.