Common mouse models of chronic kidney disease are not associated with cachexia.

The 5/6 nephrectomy and adenine-induced nephropathy mouse models have been extensively used to study Chronic Kidney Disease (CKD)-related cachexia. One common caveat of these CKD models is the cross-sectional nature of comparisons made versus controls. We here performed a comprehensive longitudinal assessment of body composition and energy metabolism in both models. The most striking finding is that weight loss is largely driven by reduced food intake which promotes rapid loss of lean and fat mass. However, in both models, mice catch up weight and lean mass a few days after the surgery or when they are switched back to standard chow diet. Muscle force and mass are fully recovered and no sign of cachexia is observed. Our data demonstrate that the time-course of kidney failure and weight loss are unrelated in these common CKD models. These data highlight the need to reconsider the relative contribution of direct and indirect mechanisms to muscle wasting observed in CKD.

Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.

Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance.

A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined.

Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans.

We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise-stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.