Individuals with type 2 diabetes are at higher risk of osteoporosis and major bone fractures independent of their body mass index (BMI). Bone marrow derived mesenchymal stem/ stromal cells (BMSC) derived from these patients exhibit reduced osteogenic potential and increased cell death. Currently, it is not known how high fat/glucose levels can suppress BMSC osteogenic differentiation potential. The present project examined the epigenetic mechanisms regulating BMSC dysfunction in response to high fat/glucose to identify targets for reversing high fat-mediated bone loss. We hypothesize that high fat/glucose levels lead to changes in BMSC epigenetic gene expression patterns that cause compromised bone formation. Ten-eleven translocation (Tet) family is a group of DNA demethylases, able to convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), an epigenetic marker in osteogenesis. Our studies have shown that TET2 is essential in driving the differentiation of bone forming osteoblasts and high glucose level inhibits the expression of TET1 and TET2. Furthermore, human BMSC grown in high glucose conditions were found to display increased level of cell death, senescence and oxidative stress, associated with decreasing cellular proliferation potential compared to BMSC cultured in regular growth media. To observe the effects of Tet molecules on bone formation in vivo, we generated a double Tet1/Tet2 knockout mouse in the mesenchymal lineage using a Prx1:Cre driver mouse. The results found that Prx1:Cre Tet1/Tet2 double knock out mice fed on high fat diet showed increased body fat and glucose tolerance and decreased bone density compared to Prx1:Cre control mice on the same diet. Understanding the role of epigenetic regulators in hyperglycaemic conditions will help to identify solutions to battle bone loss seen in diseases such as diabetes and osteoporosis. Given that epigenetic marks can be reversed by pharmacological inhibitors and altered via changes in diet and lifestyle, these targets are of unique therapeutic importance.