Metformin Affects Cortical Bone Mass and Marrow Adiposity in Diet-Induced Obesity in Male Mice

Abstract

Obesity during maturation can affect the growing skeleton directly and indirectly, although these effects and the mechanisms behind them are not fully understood. Our objective was to determine how a high-fat diet with or without metformin treatment affects skeletal development. We also sought to characterize changes that occur in white adipose tissue, circulating metabolites, lipids, and gut microbiota. A diet-induced obesity C57BL/6J mouse model was used to test the effects of obesity and metformin on bone using bone histomorphometry and microcomputed tomography. Bone marrow adipose tissue was quantified with osmium tetroxide microcomputed tomography and histology. Dual-energy x-ray absorptiometry was used to analyze body composition. Hematoxylin and eosin staining was used to assess changes in white adipose depots, mass spectrometry was used for circulating lipids and protein metabolite analysis, and ribosomal RNA sequencing was used for gut microbiome analysis. Mice fed a high fat-diet since wean displayed increased medullary areas and decreased osteoblast numbers in the long bones; this phenotype was partially normalized by metformin. Marrow and inguinal adipose expansion was also noted in obese mice, and this was partially normalized by metformin. A drug-by-diet interaction was noted for circulating lipid molecules, protein metabolites, and gut microbiome taxonomical units. Obesity was not detrimental to trabecular bone in growing mice, but bone marrow medullary expansion was observed, likely resulting from inhibition of osteoblastogenesis, and this was partially reversed by metformin treatment.

High-Fat Diet–Induced Obesity Promotes Expansion of Bone Marrow Adipose Tissue and Impairs Skeletal Stem Cell Functions in Mice

“…These discrepancies can be explained by variations in experimental models, e.g., mouse strain, sex, length/type/composition of diet (60% versus 45% fat or 10% corn oil), and possibly evaluation methods. However, the consistency observed in our study and some of the previous studies, as well as the recent study of Bornstein and colleagues reported HFD induced reduction in the cortical and trabecular parameters in the long bones along with increased BMAT volume, suggesting that bone mass reduction is a biological consequence of coherent mechanisms of cellular and molecular changes relevant for studies of bone fragility in human obesity …”

“…Similar to other investigators studying BMAT in mice and humans, we observed that HFD increased BMAT formation as evidenced by increased BMAT volume, adipocyte number, and size . In addition, we observed significant and consistent decrease in trabecular and cortical bone mass after 12 weeks of HFD.…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Studies utilizing various in vivo models of insulin resistance and/or hyperglycemia also generally confirm that metformin monotherapy is bone‐friendly, with ability to counteract the detrimental effects of diabetes on bone. Specifically, metformin has been shown to prevent or correct the diabetes‐induced alterations in bone microarchitecture and/or bone histology in models of partial insulin deficiency and in models of insulin resistance, diet‐induced obesity, or metabolic syndrome . At the same time, bone marrow adipose expansion, characteristic of mice fed a high‐fat diet, was also correctible with metformin .…”

“…Specifically, metformin has been shown to prevent or correct the diabetes‐induced alterations in bone microarchitecture and/or bone histology in models of partial insulin deficiency and in models of insulin resistance, diet‐induced obesity, or metabolic syndrome . At the same time, bone marrow adipose expansion, characteristic of mice fed a high‐fat diet, was also correctible with metformin . Finally, metformin treatment appears to accelerate wound healing and angiogenesis in hyperglycemic rodents .…”

“…[142][143][144][145] At the same time, bone marrow adipose expansion, characteristic of mice fed a high-fat diet, was also correctible with metformin. 143 Finally, metformin treatment appears to accelerate wound healing and angiogenesis in hyperglycemic rodents. 146,147 These findings, however, may be indirectly mediated by the insulinsensitizing and/or glucose-lowering efficacy of metformin in these studies.…”