Caloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice.

Introduction: Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardio-metabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure and its endocrine profile in the context of aging. Methods: Young and aged male C57Bl6J mice were subjected to CR for 8 weeks and were compared to age-matched littermates with free food access. We assessed bone microstructure and BMAT by micro-CT, bone fatty acid and transcriptomic profiles, and bone healing. Results: CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice. Discussion: Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

Lipedema stage affects adipocyte hypertrophy, subcutaneous adipose tissue inflammation and interstitial fibrosis.

Introduction: Lipedema is a painful subcutaneous adipose tissue (SAT) disease characterized by adipocyte hypertrophy, immune cell recruitment, and fibrosis in the affected areas. These features are thought to contribute to the development and progression of the condition. However, the relationship between lipedema disease stage and the associated adipose tissue changes has not been determined so far. Methods: SAT biopsies of 32 lipedema patients, ranging across the pathological stages I to III, and 14 BMI- and age-matched controls were harvested from lipedema-affected thighs and non-symptomatic lower abdominal regions. Histological and immunohistochemical (IHC) staining and expression analysis of markers for adipogenesis, immunomodulation, and fibrosis were performed on the tissue biopsies. Results: Lipedema patients showed increased adipocyte areas and a stage-dependent shift towards larger cell sizes in the thighs. Lipedema SAT was linked with increased interstitial collagen accumulation in the thighs, but not the lower abdominal region when compared to controls. There was a trend toward progressive SAT fibrosis of the affected thighs with increasing lipedema stage. Elevated gene expression levels of macrophage markers were found for thigh SAT biopsies, but not in the abdominal region. IHC staining of lipedema thigh biopsies confirmed a transiently elevated macrophage polarization towards an M2-like (anti-inflammatory) phenotype. Conclusions: In summary, lipedema SAT is associated with stage-dependent adipocyte hypertrophy, stage-progressive interstitial fibrosis and elevated proportion of M2-like macrophages. The character of the inflammatory response differs from primary obesity and may possess an essential role in the development of lipedema.

Distinct Adipogenic and Fibrogenic Differentiation Capacities of Mesenchymal Stromal Cells from Pancreas and White Adipose Tissue.

Pancreatic steatosis associates with ß-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals.

Matching Dietary Amino Acid Balance to the In Silico-Translated Exome Optimizes Growth and Reproduction without Cost to Lifespan.

Balancing the quantity and quality of dietary protein relative to other nutrients is a key determinant of evolutionary fitness. A theoretical framework for defining a balanced diet would both reduce the enormous workload to optimize diets empirically and represent a breakthrough toward tailoring diets to the needs of consumers. Here, we report a simple and powerful in silico technique that uses the genome information of an organism to define its dietary amino acid requirements. We show for the fruit fly Drosophila melanogaster that such "exome-matched" diets are more satiating, enhance growth, and increase reproduction relative to non-matched diets. Thus, early life fitness traits can be enhanced at low levels of dietary amino acids that do not impose a cost to lifespan. Exome matching also enhanced mouse growth, indicating that it can be applied to other organisms whose genome sequence is known.

Dietary Protein, Metabolism, and Aging.

Dietary restriction (DR), a moderate reduction in food intake, improves health during aging and extends life span across multiple species. Specific nutrients, rather than overall calories, mediate the effects of DR, with protein and specific amino acids (AAs) playing a key role. Modulations of single dietary AAs affect traits including growth, reproduction, physiology, health, and longevity in animals. Epidemiological data in humans also link the quality and quantity of dietary proteins to long-term health. Intricate nutrient-sensing pathways fine tune the metabolic responses to dietary AAs in a highly conserved manner. In turn, these metabolic responses can affect the onset of insulin resistance, obesity, neurodegenerative disease, and other age-related diseases. In this review we discuss how AA requirements are shaped and how ingested AAs regulate a spectrum of homeostatic processes. Finally, we highlight the resulting opportunity to develop nutritional strategies to improve human health during aging.

A holidic medium for Drosophila melanogaster.

A critical requirement for research using model organisms is a well-defined and consistent diet. There is currently no complete chemically defined (holidic) diet available for Drosophila melanogaster. We describe a holidic medium that is equal in performance to an oligidic diet optimized for adult fecundity and lifespan. This holidic diet supports development over multiple generations but at a reduced rate. Over 7 years of experiments, the holidic diet yielded more consistent experimental outcomes than did oligidic food for egg laying by females. Nutrients and drugs were more available to flies in holidic medium and, similar to dietary restriction on oligidic food, amino acid dilution increased fly lifespan. We used this holidic medium to investigate amino acid-specific effects on food-choice behavior and report that folic acid from the microbiota is sufficient for Drosophila development.