MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O2 underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction.

Ectopic Leptin Production by Intraocular Pancreatic Islet Organoids Ameliorates the Metabolic Phenotype of ob/ob Mice

The pancreatic islets of Langerhans consist of endocrine cells that secrete peptide hormones into the blood circulation in response to metabolic stimuli. When transplanted into the anterior chamber of the eye (ACE), pancreatic islets engraft and maintain morphological features of native islets as well as islet-specific vascularization and innervation patterns. In sufficient amounts, intraocular islets are able to maintain glucose homeostasis in diabetic mice. Islet organoids (pseudo-islets), which are formed by self-reassembly of islet cells following disaggregation and genetic manipulation, behave similarly to native islets. Here, we tested the hypothesis that genetically engineered intraocular islet organoids can serve as production sites for leptin. To test this hypothesis, we chose the leptin-deficient ob/ob mouse as a model system, which becomes severely obese, hyperinsulinemic, hyperglycemic, and insulin resistant. We generated a Tet-OFF-based beta-cell-specific adenoviral expression construct for mouse leptin, which allowed efficient transduction of native beta-cells, optical monitoring of leptin expression by co-expressed fluorescent proteins, and the possibility to switch-off leptin expression by treatment with doxycycline. Intraocular transplantation of islet organoids formed from transduced islet cells, which lack functional leptin receptors, to ob/ob mice allowed optical monitoring of leptin expression and ameliorated their metabolic phenotype by improving bodyweight, glucose tolerance, serum insulin, and C-peptide levels.

An Update on the Role of Leptin in the Immuno-Metabolism of Cartilage

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration.

A White Grape Juice Extract Reduces Fat Accumulation through the Modulation of Ghrelin and Leptin Expression in an In Vivo Model of Overfed Zebrafish

A caloric surplus and a sedentary lifestyle are undoubtedly known to be the leading causes of obesity. Natural products represent valuable allies to face this problematic issue. This study was planned to assess the effect of a white grape (Vitis vinifera) juice extract (WGJe) in diet-induced obese zebrafish (Danio rerio). Fish were divided into four different diet groups: (i) normally fed (NF); (ii) overfed (OF); (iii) WGJe-supplemented NF (5 mL/L in fish water); (iv) WGJe-supplemented OF. Body mass index (BMI) was extrapolated each week. After the fourth week, euthanized zebrafish were processed for both microscopic evaluations and gene expression analyses. OF zebrafish showed higher BMI values with respect to NF counterparts, an effect that was hindered by WGJe treatment. Moreover, histological analyses showed that the area of the adipose tissue, as well as the number, size, and density of adipocytes was significantly higher in OF fish. On the other hand, WGJe was able to avoid these outcomes both at the subcutaneous and visceral levels, albeit to different extents. At the gene level, WGJe restored the altered levels of ghrelin and leptin of OF fish both in gut and brain. Overall, our results support the anti-obesity property of WGJe, suggesting its potential role in weight management.

Estrogen as a Contributing Factor to the Development of Lipedema

Lipedema is an underdiagnosed painful adipose tissue disorder that occurs almost exclusively in women, with onset manifesting at puberty or at times of hormonal change. Unlike many fat disorders, diet and exercise have little to no impact on the prevention or progression of this disease. Estrogens control the distribution of body fat and food intake, regulate leptin expression, increase insulin sensitivity, and reduce inflammation through signaling pathways mediated by its receptors, estrogen receptor alpha (ERα) and ERβ. This review will focus on understanding the role of estrogen in the pathogenesis of the disease and envisage potential hormonal therapy for lipedema patients.

Increased Estradiol Levels Effect on Leptin Expression in Midluteal Endometrial Tissue of Macaca Nemestrina (Southern Pig-Tailed Macaques)

Objective: To measure the effect of serum estradiol (E2) levels on leptin expression in Macaca nemestrina (southern pig-tailed macaque) endometrial tissue. Materials and methods: This study used paraffin-embedded midluteal phase endometrial tissue blocks of Macaca nemestrina from previous study. Included subjects were 15 female macaques of reproductive age (8-10 years) with a previous history of producing offspring, which were divided into four groups: groups administered with 30 IU, 50 IU, and 70 IU r-FSH (intervention group), and no r-FSH (control group). The stimulation was done following GnRH agonist long protocol. Staining was done using immunohistochemistry. Leptin expression was measured using immunohistochemistry (IHC) Profiler plugin of ImageJ software and counted semi-quantitatively as Histological Score (Hscore). Results: Correlation between E2 concentration to stromal leptin expression was observed (p=0.043). Conclusion: Serum estradiol concentration is found to be correlated with leptin expression in Macaca nemestrina, suggesting a mechanism of decreasing endometrial receptivity among women undergoing controlled ovarian hyperstimulation.