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Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Background: Micro-RNAs could provide great insights about the neuropathological mechanisms associated with osteoarthritis (OA) pain processing. Using the validated Montreal Induction of Rat Arthritis Testing (MIRAT) model, this study aimed to characterize neuroepigenetic markers susceptible to correlate with innovative pain functional phenotype and targeted neuropeptide alterations. Methods: Functional biomechanical, somatosensory sensitization (peripheral--via tactile paw withdrawal threshold; central--via response to mechanical temporal summation), and diffuse noxious inhibitory control (via conditioned pain modulation) alterations were assessed sequentially in OA (n = 12) and Naïve (n = 12) rats. Joint structural, targeted spinal neuropeptides and differential expression of spinal cord micro-RNAs analyses were conducted at the sacrifice (day (D) 56). Results: The MI-RAT model caused important structural damages (reaching 35.77% of cartilage surface) compared to the Naïve group (P < 0.001). This was concomitantly associated with nociceptive sensitization: ipsilateral weight shift to the contralateral hind limb (asymmetry index) from -55.61% ± 8.50% (D7) to -26.29% ± 8.50% (D35) (P < 0.0001); mechanical pain hypersensitivity was present as soon as D7 and persisting until D56 (P < 0.008); central sensitization was evident at D21 (P = 0.038); pain endogenous inhibitory control was distinguished with higher conditioned pain modulation rate (P < 0.05) at D7, D21, and D35 as a reflect of filtrated pain perception. Somatosensory profile alterations of OA rats were translated in a persistent elevation of pro-nociceptive neuropeptides substance P and bradykinin, along with an increased expression of spinal miR-181b (P = 0.029) at D56. Conclusion: The MI-RAT OA model is associated, not only with structural lesions and static weight-bearing alterations, but also with a somatosensory profile that encompasses pain centralized sensitization, associated to active endogenous inhibitory/facilitatory controls, and corresponding neuropeptidomic and neuroepigenetic alterations. This preliminary neuroepigenetic research confirms the crucial role of pain endogenous inhibitory control in the development of OA chronic pain (not only hypersensitivity) and validates the MI-RAT model for its study. [ABSTRACT FROM AUTHOR]

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Simple Summary: Feline osteoarthritis (OA) diagnosis depends greatly on owner perception and experience of the disease. Owners frequently consider the emergence of OA (delayed and severe) signs as "normal" for an aged cat. Being an incurable, progressive, degenerative process, OA will require life-long treatment. There is a need for a rapid, reliable, and inexpensive diagnostic tool that reveals feline OA pain. A refined scale, the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians (MI-CAT(V)) presented remarkable metrological properties (specific, sensitive, and reliable) over its development and validation process. In particular, MI-CAT(V) was responsive to a treatment with firocoxib, a non-steroidal anti-inflammatory drug (NSAID), and discriminated four degrees of OA pain functional severity. Firocoxib presented a clear treatment effect based on the MI-CAT(V) and on other functional objective assessments, including possible dose-response. The NSAID was safe over the three-week daily administration tested period. The cluster repartition offers new perspective for an individualized treatment care. Veterinarians face the lack of a rapid, reliable, inexpensive, and treatment-sensitive metrological instrument reflecting feline osteoarthritis (OA) pain. The Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians (MI-CAT(V)) has been refined in 4 sub-sections, and we proposed its concurrent validation. Cats naturally affected by OA (n = 32) were randomly distributed into 4 groups of firocoxib analgesic (Gr. A: 0.40; B: 0.25; C: 0.15, and P: 0.00 mg/kg bodyweight). They were assessed during Baseline, Treatment, and Recovery periods using MI-CAT(V) and objective outcomes (effort path, stairs assay compliance, and actimetry). The MI-CAT(V) total score correlated to the effort path and actimetry (RhoS = −0.501 to −0.453; p < 0.001), also being sensitive to treatment responsiveness. The pooled treatment group improved its total, gait, and body posture scores during Treatment compared to the Baseline, Recovery, and placebo group (p < 0.05). The MI-CAT(V) suggested a dose-(especially for Gr. B) and cluster-response. Cats in the moderate and severe MI-CAT(V) clusters responded to firocoxib with a remaining analgesic effect, while the mild cluster seemed less responsive and experienced a negative rebound effect. The MI-CAT(V) was validated for its OA pain severity discriminatory abilities and sensitivity to firocoxib treatment, providing a new perspective for individualized care. [ABSTRACT FROM AUTHOR]

Validating animal pain models is crucial to enhancing translational research and response to pharmacological treatment. This study investigated the effects of a calibrated slight exercise protocol alone or combined with multimodal analgesia on sensory sensitivity, neuroproteomics, and joint structural components in the MI-RAT model. Joint instability was induced surgically on day (D) 0 in female rats (N = 48) distributed into sedentary–placebo, exercise–placebo, sedentary–positive analgesic (PA), and exercise–PA groups. Daily analgesic treatment (D3–D56) included pregabalin and carprofen. Quantitative sensory testing was achieved temporally (D–1, D7, D21, D56), while cartilage alteration (modified Mankin's score (mMs)) and targeted spinal pain neuropeptide were quantified upon sacrifice. Compared with the sedentary–placebo (presenting allodynia from D7), the exercise–placebo group showed an increase in sensitivity threshold (p < 0.04 on D7, D21, and D56). PA treatment was efficient on D56 (p = 0.001) and presented a synergic anti-allodynic effect with exercise from D21 to D56 (p < 0.0001). Histological assessment demonstrated a detrimental influence of exercise (mMs = 33.3%) compared with sedentary counterparts (mMs = 12.0%; p < 0.001), with more mature transformations. Spinal neuropeptide concentration was correlated with sensory sensitization and modulation sites (inflammation and endogenous inhibitory control) of the forced mobility effect. The surgical MI-RAT OA model coupled with calibrated slight exercise demonstrated face and predictive validity, an assurance of higher clinical translatability. [ABSTRACT FROM AUTHOR]

Maladaptive wound healing responses to chronic tissue injury result in organ fibrosis. Fibrosis, which entails excessive extracellular matrix (ECM) deposition and tissue remodeling by activated myofibroblasts, leads to loss of proper tissue architecture and organ function; however, the molecular mediators of myofibroblast activation have yet to be fully identified. Here we identify soluble ephrin-B2 (sEphrin-B2) as a new profibrotic mediator in lung and skin fibrosis. We provide molecular, functional and translational evidence that the ectodomain of membrane-bound ephrin-B2 is shed from fibroblasts into the alveolar airspace after lung injury. Shedding of sEphrin-B2 promotes fibroblast chemotaxis and activation via EphB3 and/or EphB4 receptor signaling. We found that mice lacking ephrin-B2 in fibroblasts are protected from skin and lung fibrosis and that a disintegrin and metalloproteinase 10 (ADAM10) is the major ephrin-B2 sheddase in fibroblasts. ADAM10 expression is increased by transforming growth factor (TGF)-[beta]1, and ADAM10-mediated sEphrin-B2 generation is required for TGF-[beta]1-induced myofibroblast activation. Pharmacological inhibition of ADAM10 reduces sEphrin-B2 levels in bronchoalveolar lavage and prevents lung fibrosis in mice. Consistent with the mouse data, ADAM10-sEphrin-B2 signaling is upregulated in fibroblasts from human subjects with idiopathic pulmonary fibrosis. These results uncover a new molecular mechanism of tissue fibrogenesis and identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases., Author(s): David Lagares (corresponding author) [1]; Parisa Ghassemi-Kakroodi [2]; Caroline Tremblay [2]; Alba Santos [1]; Clemens K Probst [1]; Alicia Franklin [1]; Daniela M Santos [1]; Paula Grasberger [1]; Neil [...]