CHKB encodes one of two mammalian choline kinase enzymes that catalyze the first step in the synthesis of the membrane phospholipid phosphatidylcholine. In humans and mice, inactivation of the CHKB gene (Chkb in mice) causes a recessive rostral-to-caudal muscular dystrophy. Using Chkb knockout mice, we reveal that at no stage of the disease is phosphatidylcholine level significantly altered. We observe that in affected muscle a temporal change in lipid metabolism occurs with an initial inability to utilize fatty acids for energy via mitochondrial β-oxidation resulting in shunting of fatty acids into triacyglycerol as the disease progresses. There is a decrease in peroxisome proliferator-activated receptors and target gene expression specific to Chkb−/− affected muscle. Treatment of Chkb−/− myocytes with peroxisome proliferator-activated receptor agonists enables fatty acids to be used for β-oxidation and prevents triacyglyerol accumulation, while simultaneously increasing expression of the compensatory choline kinase alpha (Chka) isoform, preventing muscle cell injury.

When compared to adipocytes in other anatomical sites, the interaction of bone marrow resident adipocytes with the other cells in their microenvironment is less well understood. Bone marrow adipocytes originate from a resident, self-renewing population of multipotent bone marrow stromal cells which can also give rise to other lineages such as osteoblasts. The differentiation fate of these mesenchymal progenitors can be influenced to favour adipogenesis by several factors, including the administration of thiazolidinediones and increased age. Experimental data suggests that increases in bone marrow adipose tissue volume may make bone both more attractive to metastasis and conducive to cancer cell growth. Bone marrow adipocytes are known to secrete a variety of lipids, cytokines and bioactive signaling molecules known as adipokines, which have been implicated as mediators of the interaction between adipocytes and cancer cells. Recent studies have provided new insight into the impact of bone marrow adipose tissue volume expansion in regard to supporting and exacerbating the effects of bone metastasis from solid tumors, focusing on prostate, breast and lung cancer and blood cancers, focusing on multiple myeloma. In this mini-review, recent research developments pertaining to the role of factors which increase bone marrow adipose tissue volume, as well as the role of adipocyte secreted factors, in the progression of bone metastatic prostate and breast cancer are assessed. In particular, recent findings regarding the complex cross-talk between adipocytes and metastatic cells of both lung and prostate cancer are highlighted.

Background The incidence of Inflammatory Bowel Disease (IBD) among the obese pediatric populations is increasing. Succinate has been identified as a possible metabolite linking the two diseases. Succinate receptor 1 (SUCNR1) gene knockout (KO) mice are less susceptible to dextran sulfate sodium (DSS)-induced colitis. Aims To determine whether succinate plays a role in mice becoming obese and colitis in obesity, and whether an obese-inducing diet would change the gut microbiota. We hypothesized that SUCNR1-KO mice would not become obese and would experience less colonic inflammation despite the diet. Methods C57BL/6 (WT) were bred with SUCNR1-KO mice (generously provided by Amgen), and the heterozygous (HZ) F1 offspring bred to obtain F2. Two of 3 F2 litters included SUCNR1-KO mice, which were caged by sex but not genotype. These F2 mice began a high-fat/high-sugar (obese, Dytes) diet at 5 wks of age for 5 wks. Weights were recorded and stool collected. All mice then had 3% DSS replace their water, for 5 days. Mice were observed for diarrhea and occult blood. After the DSS, facility water was returned for 1 day prior to postmortem analyses. Mice were scanned using dual-energy X-ray absorptiometry (DEXA) for measures of fat, lean and fat mass, and bone density. Their colons were resected and fixed for histopathology. Stool was banked frozen until processed for sequencing using 16S Ribosomal primers. Results Three F2 litters were comprised of ratios of HZ:WT:SUCNR1-KO of 14:7:2. SUCNR1-KO mice (n=2 female) had a greater increase in weight compared to other genotypes during the obesity-induction phase. Weight loss during the DSS phase was similar across all genotypes. All mice had blood in their stool. DEXA measures did not differ between genotypes. All genotypes of mice had inflamed colons. Conclusions SUCNR1-KO mice are not resistant to obesity, nor from colitis when consuming the obese diet, outcomes that do not support our hypothesis. It remains to be determined whether the diet alters the microbiome resulting in SUCNR1-KO mice being suscueptible to colitis. Microbial sequencing is underway. Funding Agencies IWK Health Project Grant