Vitamin D metabolism is altered during aging alone or combined with obesity in male mice.

Aging and obesity are associated with a decrease in plasma 25-hydroxyvitamin D (25(OH)D) levels. In the context of a growing aging population and the rising incidence of obesity, we hypothesized that aging process, either independently or in combination with obesity, could influence vitamin D (VD) metabolism, consequently resulting in the reduced 25(OH)D plasma concentrations. C57BL/6JRJ young (6 months) and old (23 months) mice fed with control (CD) or high fat diet (HF) were compared. Plasma and adipose concentration of cholecalciferol and 25(OH)D and mRNA expression of genes coding for the main VD actors were analyzed. Aging was associated with a decrease in plasma 25(OH)D levels, whereas combined effect of obesity and aging did not generate a cumulative effect on plasma 25(OH)D levels. The mRNA expression of Cyp27a1, Cyp3a11, and Cyp2j6 were decreased in the liver during aging. Together, these regulations could explain the reduced 25-hydroxylation. Interestingly, the lack of cumulative reduction of 25(OH)D in aged and obese mice could be related to the strong induction of Cyp2j6. In kidneys, a complex modulation of Cyp27b1 and Cyp24a1 could contribute to the reduced 25-hydroxylation in the liver. In white adipose tissue, an induction of Cyp2r1 was observed during aging and obesity, together with an increase of 25(OH)D quantity, suggesting an exacerbated storage that may participated to the reduced plasma 25(OH)D levels. These findings support the notion that aging alone or combined with obesity, induces regulation of VD metabolism in the organs, beyond the classical reduction of epidermal VD precursor, which may contribute to the decrease in 25(OH)D levels.

Low-Intensity Running and High-Intensity Swimming Exercises Differentially Improve Energy Metabolism in Mice With Mild Spinal Muscular Atrophy.

Spinal Muscular Atrophy (SMA), an autosomal recessive neurodegenerative disease characterized by the loss of spinal-cord motor-neurons, is caused by mutations on Survival-of-Motor Neuron (SMN)-1 gene. The expression of SMN2, a SMN1 gene copy, partially compensates for SMN1 disruption due to exon-7 excision in 90% of transcripts subsequently explaining the strong clinical heterogeneity. Several alterations in energy metabolism, like glucose intolerance and hyperlipidemia, have been reported in SMA at both systemic and cellular level, prompting questions about the potential role of energy homeostasis and/or production involvement in disease progression. In this context, we have recently reported the tolerance of mild SMA-like mice (SmnΔ7/Δ7; huSMN2 +/+) to 10 months of low-intensity running or high-intensity swimming exercise programs, respectively involving aerobic and a mix aerobic/anaerobic muscular metabolic pathways. Here, we investigated whether those exercise-induced benefits were associated with an improvement in metabolic status in mild SMA-like mice. We showed that untrained SMA-like mice exhibited a dysregulation of lipid metabolism with an enhancement of lipogenesis and adipocyte deposits when compared to control mice. Moreover, they displayed a high oxygen consumption and energy expenditure through ß-oxidation increase yet for the same levels of spontaneous activity. Interestingly, both exercises significantly improved lipid metabolism and glucose homeostasis in SMA-like mice, and enhanced oxygen consumption efficiency with the maintenance of a high oxygen consumption for higher levels of spontaneous activity. Surprisingly, more significant effects were obtained with the high-intensity swimming protocol with the maintenance of high lipid oxidation. Finally, when combining electron microscopy, respiratory chain complexes expression and enzymatic activity measurements in muscle mitochondria, we found that (1) a muscle-specific decreased in enzymatic activity of respiratory chain I, II, and IV complexes for equal amount of mitochondria and complexes expression and (2) a significant decline in mitochondrial maximal oxygen consumption, were reduced by both exercise programs. Most of the beneficial effects were obtained with the high-intensity swimming protocol. Taking together, our data support the hypothesis that active physical exercise, including high-intensity protocols, induces metabolic adaptations at both systemic and cellular levels, providing further evidence for its use in association with SMN-overexpressing therapies, in the long-term care of SMA patients.

Long-term exercise-specific neuroprotection in spinal muscular atrophy-like mice.

KEY POINTS: The real impact of physical exercise parameters, i.e. intensity, type of contraction and solicited energetic metabolism, on neuroprotection in the specific context of neurodegeneration remains poorly explored. In this study behavioural, biochemical and cellular analyses were conducted to compare the effects of two different long-term exercise protocols, high intensity swimming and low intensity running, on motor units of a type 3 spinal muscular atrophy (SMA)-like mouse model. Our data revealed a preferential SMA-induced death of intermediate and fast motor neurons which was limited by the swimming protocol only, suggesting a close relationship between neuron-specific protection and their activation levels by specific exercise. The exercise-induced neuroprotection was independent of SMN protein expression and associated with specific metabolic and behavioural adaptations with notably a swimming-induced reduction of muscle fatigability. Our results provide new insight into the motor units' adaptations to different physical exercise parameters and will contribute to the design of new active physiotherapy protocols for patient care. ABSTRACT: Spinal muscular atrophy (SMA) is a group of autosomal recessive neurodegenerative diseases differing in their clinical outcome, characterized by the specific loss of spinal motor neurons, caused by insufficient level of expression of the protein survival of motor neuron (SMN). No cure is at present available for SMA. While physical exercise might represent a promising approach for alleviating SMA symptoms, the lack of data dealing with the effects of different exercise types on diseased motor units still precludes the use of active physiotherapy in SMA patients. In the present study, we have evaluated the efficiency of two long-term physical exercise paradigms, based on either high intensity swimming or low intensity running, in alleviating SMA symptoms in a mild type 3 SMA-like mouse model. We found that 10 months' physical training induced significant benefits in terms of resistance to muscle damage, energetic metabolism, muscle fatigue and motor behaviour. Both exercise types significantly enhanced motor neuron survival, independently of SMN expression, leading to the maintenance of neuromuscular junctions and skeletal muscle phenotypes, particularly in the soleus, plantaris and tibialis of trained mice. Most importantly, both exercises significantly improved neuromuscular excitability properties. Further, all these training-induced benefits were quantitatively and qualitatively related to the specific characteristics of each exercise, suggesting that the related neuroprotection is strongly dependent on the specific activation of some motor neuron subpopulations. Taken together, the present data show significant long-term exercise benefits in type 3 SMA-like mice providing important clues for designing rehabilitation programmes in patients.

Acute oral metformin enhances satiation and activates brainstem nesfatinergic neurons.

OBJECTIVE: The study was designed to determine metformin effects on meal pattern, gastric emptying, energy expenditure, and to identify metformin-sensitive neurons and their phenotype. METHODS: This study was performed on C57BL/6J and obese/diabetic (db/db) mice. Metformin (300 mg/kg) was administered by oral gavage. Food intake, meal pattern, oxygen consumption (VO2 ), and carbon dioxide production (VCO2 ) were obtained using an Oxylet Physiocage System. Gastric emptying assay and real-time RT-PCR from dorsal vagal complex extracts were also performed. C-Fos expression was used as a marker of neuronal activation. Phenotypic characterization of activated neurons was performed using either proopiomelanocortin (POMC)-Tau-Topaz GFP transgenic mice or NUCB2/nesfatin-1 and tyrosine hydroxylase (TH) labeling. RESULTS: Acute per os metformin treatment slowed down gastric emptying, reduced meal size, but not meal number in a leptin-independent manner, and transiently decreased energy expenditure in a leptin-dependent manner. Metformin specifically activated central circuitry within the brainstem, independently of vagal afferents. Finally, while POMC neurons seemed sparsely activated, we report that a high proportion of the c-Fos positive cells were nesfatinergic neurons, some of which coexpressing TH. CONCLUSIONS: Altogether, these results show that metformin modifies satiation by activating brainstem circuitry and suggest that NUCB2/nesfatin-1 could be involved in this metformin effect.

The central question of type 2 diabetes.

Type 2 diabetes (T2D) represents a significant global epidemic with more than 285 million people affected worldwide. Regulating glycemia in T2D patients can be partially achieved with currently available treatment, but intensive research during the last decades have led to the discovery of modified compounds or new targets that could represent great hope for safe and effective treatment in the future. Among them, targets in the CNS that are known to control feeding and body weight have been also shown to exert glucoregulatory actions, and could be a key in the development of a new generation of drugs in the field of T2D. Such drugs would be of great interest since they can be used both in the treatment of diabetes and obesity. This patent review aims to establish an overview of recent patents disclosing new therapeutic opportunities targeting peripheral, as well as central targets for the treatment of T2D.