Collagen fiber orientation is related to strain mode and may function to accentuate rather than attenuate bending. These differences may represent adaptations that function synergistically with bone geometry to promote a beneficial strain distribution and loading predictability during functional loading.

Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways. RNA-sequencing of adipose tissue macrophages demonstrated a role for miR-146a in regulating both inflammation and cellular metabolism, including the mTOR pathway, during obesity. Further, we demonstrate that miR-146a regulates inflammation, cellular respiration and glycolysis in macrophages through a mechanism involving its direct target Traf6 . Finally, we found that administration of rapamycin, an inhibitor of mTOR, was able to rescue the obesity phenotype in miR-146a-/- mice. Altogether, our study provides evidence that miR-146a represses inflammation and diet-induced obesity and regulates metabolic processes at the cellular and organismal levels, demonstrating how the combination of diet and miRNA genetics influences obesity and diabetic phenotypes.

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Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.

Macrophages are key cells of the innate immune system with functional roles in both homeostatic maintenance of self-tissues and inflammatory responses to external stimuli, including infectious agents. Recent advances in metabolic research have revealed that macrophage functions rely upon coordinated metabolic programs to regulate gene expression, inflammation, and other important cellular processes. Polarized macrophages adjust their use of nutrients such as glucose and amino acids to meet their changing metabolic needs, and this in turn supports the functions of the activated macrophage. Metabolic and inflammatory processes have been widely studied, and a crucial role for their regulation at the post-transcriptional level by microRNAs (miRNAs) has been identified. miRNAs govern many facets of macrophage biology, including direct targeting of metabolic regulators and inflammatory pathways. This review will integrate emerging data that support an interplay between miRNAs and metabolism during macrophage inflammatory responses, highlighting critical miRNAs and miRNA families. Additionally, we will address the implications of these networks for human disease and discuss emerging areas of research in this field.