Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism.

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight loss is fat mass, there is also a loss of lean mass, similar to other approaches that induce calorie deficit. Targeting signaling pathways that regulate skeletal muscle hypertrophy is a promising avenue to preserve lean mass and modulate body composition. Myostatin and Activin A are TGFß-like ligands that signal via the activin type II receptors (ActRII) to antagonize muscle growth. Pre-clinical and clinical studies demonstrate that ActRII blockade induces skeletal muscle hypertrophy and reduces fat mass. In this manuscript, we test the hypothesis that combined ActRII blockade and GLP-1 receptor agonism will preserve muscle mass, leading to improvements in skeletomuscular and metabolic function and enhanced fat loss. METHODS: In this study, we explore the therapeutic potential of bimagrumab, a monoclonal antibody against ActRII, to modify body composition alone and during weight loss induced by GLP-1 receptor agonist semaglutide in diet-induced obese mice. Mechanistically, we define the specific role of the anabolic kinase Akt in mediating the hypertrophic muscle effects of ActRII inhibition in vivo. RESULTS: Treatment of obese mice with bimagrumab induced a ∼10 % increase in lean mass while simultaneously decreasing fat mass. Daily treatment of obese mice with semaglutide potently decreased body weight; this included a significant decrease in both muscle and fat mass. Combination treatment with bimagrumab and semaglutide led to superior fat mass loss while simultaneously preserving lean mass despite reduced food intake. Treatment with both drugs was associated with improved metabolic outcomes, and increased lean mass was associated with improved exercise performance. Deletion of both Akt isoforms in skeletal muscle modestly reduced, but did not prevent, muscle hypertrophy driven by ActRII inhibition. CONCLUSIONS: Collectively, these data demonstrate that blockade of ActRII signaling improves body composition and metabolic parameters during calorie deficit driven by GLP-1 receptor agonism and demonstrate the existence of Akt-independent pathways supporting muscle hypertrophy in the absence of ActRII signaling.

Inhibition of nucleotide biosynthesis disrupts lipid accumulation and adipogenesis.

Energy balance and nutrient availability are key determinants of cellular decisions to remain quiescent, proliferate, or differentiate into a mature cell. After assessing its environmental state, the cell must rewire its metabolism to support distinct cellular outcomes. Mechanistically, how metabolites regulate cell fate decisions is poorly understood. We used adipogenesis as our model system to ascertain the role of metabolism in differentiation. We isolated adipose tissue stromal vascular fraction cells and profiled metabolites before and after adipogenic differentiation to identify metabolic signatures associated with these distinct cellular states. We found that differentiation alters nucleotide accumulation. Furthermore, inhibition of nucleotide biosynthesis prevented lipid storage within adipocytes and downregulated the expression of lipogenic factors. In contrast to proliferating cells, in which mechanistic target of rapamycin complex 1 is activated by purine accumulation, mechanistic target of rapamycin complex 1 signaling was unaffected by purine levels in differentiating adipocytes. Rather, our data indicated that purines regulate transcriptional activators of adipogenesis, peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α, to promote differentiation. Although de novo nucleotide biosynthesis has mainly been studied in proliferation, our study points to its requirement in adipocyte differentiation.

Weighing in on Adipogenesis.

Obesity is a growing health concern worldwide because of its contribution to metabolic syndrome, type II diabetes, insulin resistance (IR), and numerous cancers. In obesity, white adipose tissue (WAT) expands through two mechanisms: increase in adipocyte cell number by precursor cell differentiation through the process of adipogenesis (hyperplasia) and increase in existing mature adipocyte cell size (hypertrophy). While hypertrophy is associated with the negative effects of obesity on metabolic health, such as inflammation and lipotoxicity, adipogenesis prevents obesity-mediated metabolic decline. Moreover, in metabolically healthy obesity adipogenesis is increased. Thus, it is vital to understand the mechanistic basis for adipose expansion to inform novel therapeutic approaches to mitigate the dysfunction of this tissue and associated diseases. In this mini-review, we summarize recent studies on the regulation of adipogenesis and provide a perspective on targeting adipogenesis as a potential therapeutic avenue for metabolic disorders.

SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis.

Upon nutrient stimulation, pre-adipocytes undergo differentiation to transform into mature adipocytes capable of storing nutrients as fat. We profiled cellular metabolite consumption to identify early metabolic drivers of adipocyte differentiation. We find that adipocyte differentiation raises the uptake and consumption of numerous amino acids. In particular, branched-chain amino acid (BCAA) catabolism precedes and promotes peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of adipogenesis. In early adipogenesis, the mitochondrial sirtuin SIRT4 elevates BCAA catabolism through the activation of methylcrotonyl-coenzyme A (CoA) carboxylase (MCCC). MCCC supports leucine oxidation by catalyzing the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. Sirtuin 4 (SIRT4) expression is decreased in adipose tissue of numerous diabetic mouse models, and its expression is most correlated with BCAA enzymes, suggesting a potential role for SIRT4 in adipose pathology through the alteration of BCAA metabolism. In summary, this work provides a temporal analysis of adipocyte differentiation and uncovers early metabolic events that stimulate transcriptional reprogramming.

Bioavailable 87Sr/86Sr in different environmental samples--effects of anthropogenic contamination and implications for isoscapes in past migration studies.

(87)Sr/(86)Sr reference maps (isoscapes) are a key tool for investigating past human and animal migrations. However, there is little understanding of which biosphere samples are best proxies for local bioavailable Sr when dealing with movements of past populations. In this study, biological and geological samples (ground vegetation, tree leaves, rock leachates, water, soil extracts, as well as modern and archeological animal teeth and snail shells) were collected in the vicinity of two early medieval cemeteries ("Thuringians", 5-6th century AD) in central Germany, in order to characterize (87)Sr/(86)Sr of the local biosphere. Animal tooth enamel is not appropriate in this specific context to provide a reliable (87)Sr/(86)Sr baseline for investigating past human migration. Archeological faunal teeth data (pig, sheep/goat, and cattle) indicates a different feeding area compared to that of the human population and modern deer teeth (87)Sr/(86)Sr suggest the influence of chemical fertilizers. Soil leachates do not yield consistent (87)Sr/(86)Sr, and (87)Sr/(86)Sr of snail shells are biased towards values for soil carbonates. In contrast, water and vegetation samples seem to provide the most accurate estimates of bioavailable (87)Sr/(86)Sr to generate Sr isoscapes in the study area. Long-term environmental archives of bioavailable (87)Sr/(86)Sr such as freshwater bivalve shells and tree cores were examined in order to track potential historic anthropogenic contamination of the water and the vegetation. The data obtained from the archeological bivalve shells show that the modern rivers yield (87)Sr/(86)Sr ratios which are similar to those of the past. However, the tree cores registered decreasing (87)Sr/(86)Sr values over time towards present day likely mirroring anthropogenic activities such as forest liming, coal mining and/or soil acidification. The comparison of (87)Sr/(86)Sr of the Thuringian skeletons excavated in the same area also shows that the vegetation samples are very likely anthropogenically influenced to some extent, affecting especially (87)Sr/(86)Sr of the shallow rooted plants.

A randomized controlled trial of telephone calls to young patients with poorly controlled type 1 diabetes.

OBJECTIVE: To determine if scheduled telephone calls from a pediatric diabetes educator to children who have type 1 diabetes improve hemoglobin A1c (HbA1c) level, hospital admissions, diabetes knowledge, compliance, and psychological well-being. RESEARCH DESIGN AND METHODS: A randomized controlled trial of 123 young subjects (mean age 11.9 yr, 69 male) with type 1 diabetes (mean duration 3.65 yr). For 7 months, the intervention group held bimonthly 15-30 min scheduled supportive telephone discussions. The primary outcome was change in the HbA1c level. Admission rates and changes in diabetes knowledge, psychological parameters, compliance, and patient perception were measured. RESULTS: There was no significant difference between the treatment and control groups either before or after the intervention. The mean HbA1c level in the control group increased from 8.32 to 8.82% and in the intervention group from 8.15 to 8.85% (p = 0.24). Both groups showed an increase in admissions of 0.2 per yr (p = 0.57). There was no improvement in diabetes knowledge (p = 0.34), compliance, or psychological function. The intervention group viewed their contact with the clinic as more helpful (p = 0.003). Analysis of family function did not reveal subgroups with statistically significant differences. A mean of 13 calls was made to each subject at a cost of 36 Australian dollars per child per month. CONCLUSIONS: Scheduled bimonthly phone support does not improve the HbA1c level, admission rates, diabetes knowledge, psychological function, or self-management but is perceived by patients as helpful. Further study into the effects of more frequent but shorter periods of support for patients experiencing specific difficulties is needed.

Parents' perspectives of health-care delivery to their chronically ill children during school.

This study sought to identify parents' perspectives about issues relating to the provision of health care to their chronically ill children while they are at school. A survey of parents with school-aged children attending the paediatric subspecialty outpatients clinic in a large teaching hospital was designed to collect both qualitative and quantitative data about this topic. Findings included that 48% (n =161) of parents participating in the study said their child required some form of care or attention while at school. Highest scoring areas of need included supervision of meals (36%), administering insulin (19%), and administering nebulizers/puffers (19%). In addition, 75% of parents with children requiring health care while in school said that special knowledge and skill was required to deliver this care; 56% of these parents did not feel that teachers had the knowledge that would enable them too look after their chronically ill child during school hours.