Distinct Effects of a High Fat Diet on Bone in Skeletally Mature and Developing Male C57BL/6J Mice

Abstract

Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.

The Influence of Obesity, Ovariectomy, and Greenshell Mussel Supplementation on Bone Mineral Density in Rats

“…( 55 , 56 , 57 ) In addition, hyperglycemia mice induced by high‐fat diet showed reduced biomechanical strength of trabecular and cortical bone with reduced expression of osteocalcin, as which the finding supported bone loss in hyperglycemia mice due to decreased bone formation (osteoblast function). ( 58 ) Therefore, decreased bone metabolism is probably the underlying mechanism driving the reduction of BMD in our OVX rats. This finding reveals the fact that there may be different subtypes of osteoporosis in postmenopausal women based on the severity of metabolic conditions and, therefore, the specific therapeutic approach should be considered for those subtypes.…”

Circulating SIRT1 and Sclerostin Correlates with Bone Status in Young Women with Different Degrees of Adiposity

“…Accordingly, either SOST -knockout mice or sclerostin-neutralizing antibody-treated mice exhibit a phenotype characterized by increased bone mass and reduced white adipose tissue [ 19 ]. Ross et al reported decreased bone formation, decreased osteocalcin expression and increased sclerostin RNA expression in young and old HFD-fed mice compared to standard chow-fed mice, confirming the negative effect exerted by metabolic diseases on bone, including through the activation of sclerostin [ 49 ].…”

Dietary Complex and Slow Digestive Carbohydrates Promote Bone Mass and Improve Bone Microarchitecture during Catch-Up Growth in Rats

“…In animals, catch-up growth was demonstrated to promote insulin resistance through dysfunction of the adipose tissue [ 41 ]. In addition, it has also been shown that hyperinsulinemia, together with an impaired control of the blood glucose levels, is associated with decreased bone mass and defective bone microarchitecture [ 14 , 42 ]. In this sense, studies conducted in streptozotocin-induced diabetic adult rats, which are characterized by induced hyperglycemia, have observed that diabetic animals display lower BMD and connection density along with compromised bone microstructure compared to control healthy rats [ 14 ].…”

“…As previously commented, unhealthy catch-up growth correlates to higher risk of metabolic diseases, such as diabetes and obesity, later in life [ 7 ]. Moreover, diabetic, and obese adult patients are at higher risk of bone fractures due to impaired bone microstructure [ 42 , 46 ]. Overall, preventing the development of a thrifty phenotype characterized by impaired insulin sensitivity might exert short- and long-term beneficial effects on bone health parameters (i.e., BMD and bone trabecular and cortical microstructure) of children undergoing catch-up growth, leading to a higher peak bone mass at the end of their adolescence.…”