Deletion of Hsd11b1 suppresses caloric-restriction-induced bone marrow adiposity in male but not female mice.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy and, notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11ß-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11ß-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restraining BMAT expansion and bone loss. To test this, we first confirmed that 11ß-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11ß-HSD1 knockout mice from 9-15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in BM. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11ß-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlight progesterone as a potential new regulator of BM adiposity.

The phospholipase A2 family's role in metabolic diseases: Focus on skeletal muscle.

The prevalence of obesity and type 2 diabetes has increased substantially in recent years creating a global health burden. In obesity, skeletal muscle, the main tissue responsible for insulin-mediated glucose uptake, exhibits dysregulation of insulin signaling, glucose uptake, lipid metabolism, and mitochondrial function, thus, promoting type 2 diabetes. The phospholipase A2 (PLA2) enzyme family mediates lipid signaling and membrane remodeling and may play an important role in metabolic disorders such as obesity, diabetes, hyperlipidemia, and fatty liver disease. The PLA2 family consists of 16 members clustered in four groups. PLA2s hydrolyze the sn-2 ester bond of phospholipids generating free fatty acids and lysophospholipids. Differential tissue and subcellular PLA2 expression patterns and the abundance of distinct fatty acyl groups in the target phospholipid determine the impact of individual family members on metabolic functions and, potentially, diseases. Here, we update the current knowledge of the role of the PLA2 family in skeletal muscle, with a view to their potential for therapeutic targeting in metabolic diseases.