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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.

Simple Summary: Feline osteoarthritis (OA) is a painful degenerative musculoskeletal disease characterised by functional alterations and degraded animal welfare. As OA cannot be cured, veterinarians' therapeutic goal is to reduce pain symptoms to better the animal's quality of life. The pharmacological arsenal is reduced in cats because of the specific therapeutic margin and the occurrence of side effects. Non-pharmacological avenues such as nutraceuticals are promising. However, there is a need for strong, evidence-based research on the effects of nutraceuticals in feline OA. The present study evaluated the efficacy and safety of a therapeutic diet containing omega-3s, hydrolysed collagen and turmeric extract with a clinical metrology instrument and three objective outcomes that were all previously validated as specific, sensitive and reliable. The diet was proven to provide a clear treatment effect in all cats, including those who were moderately and severely affected, to yield a high rate of compliance to administration and to be devoid of any side effect, which is of fundamental importance when treating chronic illnesses like OA. This study evaluated a therapeutic diet high in eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) of marine source (EPA:DHA ratio 0.69:1), turmeric extract, and hydrolysed collagen in cats (N = 30) with naturally occurring osteoarthritis (OA) over a 13-week (W) period, followed by a 4-W washout, using four previously validated pain/functional outcomes. Compared to the placebo diet, the therapeutic diet significantly improved peak vertical force (p = 0.017; W16, 64% responders), correlating to enhanced weight bearing; stair assay compliance (p < 0.001; W16, 87% responders), reflecting reduced fatigue related to OA pain; night-time actimetry (cohort effect; p = 0.05, 67% responders), suggesting greater spontaneous mobility and comfort; and MI-CAT(V) score (cohort effect; p < 0.001, 80% responders), indicating reduced functional impairments. The earliest therapeutic response was observed at W06, marked by an inflection point between actimetric linear regressions of both cohorts, confirmed by significant MI-CAT(V) differences (p < 0.007; W08; W12; W16). The MI-CAT(V) clinical metrology instrument was validated for inter-rater reliability, minimal placebo effect (<15% responders), and OA severity clustering. Despite baseline differences in biomechanical assessments (p < 0.05), both moderate and severe OA clusters responded equally positively to the therapeutic diet. Based on all outcomes, the therapeutic diet showed promise for the long-term management of feline OA, with no observed side effects. [ABSTRACT FROM AUTHOR]

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]