Effects of long term diabetogenic high fat diet on bone in ovariectomized female rats.

A diabetogenic high fat diet (HFD) can be used to induce insulin resistance and obesity in animal models; however, its effects on bone are unknown. We investigated the effects of long term HFD on bone in ovariectomized (OVX) female rats. We used 12-week-old female rats divided randomly into four groups: sham operation (sham), sham operation with HFD (SHFD), OVX and OVX with HFD (OVX + HFD). Ovaries were removed in the OVX and OVX + HFD groups and the SHFD and OVX + HFD groups were fed a HFD for 28 weeks. Serum estrogen, testosterone, lipid, adiponectin, leptin, tartrate-resistant acid phosphatase (TRAP) and N-mid fragment of osteocalcin (N-MID-OT) levels were measured. Structure, apoptosis and specific transcription factors in bone were evaluated using pathologic, densitometric and immunohistochemical analysis. Body weight, serum leptin, TRAP and testosterone levels were increased, while serum N-MID-OT, estrogen and adiponectin levels were decreased in the SHFD, OVX and OVX + HFD groups. Expression of BCL2-associated X protein, caspase-3, matrix metalloproteinase-9 and calcitonin was increased, while bone mineral density (BMD) and content (BMC) in femurs and lumbar spine, and expression of B cell lymphoma 2, type 1 collagen and osteocalcin were decreased in the bones of the SHFD, OVX and OVX + HFD groups. All indices were greatest in the OVX + HFD group and HFD produced a detrimental effect on bone in both normal and OVX rats, which may be due to increased apoptosis in bone and increased leptin and decreased adiponectin levels in serum. The effects of HFD and OVX may be synergistic.

Differential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation.

White adipose tissue (WAT) plays a role in storing energy, while brown adipose tissue (BAT) is instrumental in the re-distribution of stored energy when dietary sources are unavailable. Interleukin-18 (IL18) is a cytokine playing a role in T-cell polarization, but also for regulating energy homeostasis via the dimeric IL18 receptor (IL18r) and Na-Cl co-transporter (NCC) on adipocytes. Here we show that IL18 signaling in metabolism is regulated at the level of receptor utilization, with preferential role for NCC in brown adipose tissue (BAT) and dominantly via IL18r in WAT. In Il18r-/-Ncc-/- mice, high-fat diet (HFD) causes more prominent body weight gain and insulin resistance than in wild-type mice. The WAT insulin resistance phenotype of the double-knockout mice is recapitulated in HFD-fed Il18r-/- mice, whereas decreased thermogenesis in BAT upon HFD is dependent on NCC deletion. BAT-selective depletion of either NCC or IL18 reduces thermogenesis and increases BAT and WAT inflammation. IL18r deletion in WAT reduces insulin signaling and increases WAT inflammation. In summary, our study contributes to the mechanistic understanding of IL18 regulation of energy metabolism and shows clearly discernible roles for its two receptors in brown and white adipose tissues.

Sitagliptin Reduces Endothelial Dysfunction and Apoptosis Induced by High-Fat Diet and Palmitate in Thoracic Aortas and Endothelial Cells via ROS-ER Stress-CHOP Pathway.

Macrovascular disease is tightly associated with obesity-induced metabolic syndrome. Sitagliptin (SIT), an orally stable selective inhibitor of Dipeptidyl peptidase-4 (DPP-4), has protective effects on endothelium. However, the mechanisms enabling SIT to exhibit resistance to diet-induced obesity (DIO) related with reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress in the aorta and endothelial cells have not been reported yet. Therefore, the present study was conducted to determine if SIT exerts protective role in the thoracic aortas isolated from the high-fat diet (HFD)-treated rats and palmitate (PA)-treated endothelial cells by alleviating ROS and ER stress. Male Sprague Dawley rats were randomly divided into standard chow diet (SCD), HFD and HFD plus sitagliptin administration (HFD + SIT) groups. The rats of latter two groups were given HFD fodder for 12 weeks, then the HFD + SIT rats were treated with SIT (10 mg/kg/d) by intragastric administration for another 8 weeks. The body mass, vascular tension, serum oxidative stress indices and inflammatory parameters, pathological changes, protein expression of endothelial nitric oxide synthase (eNOS), the genes associated with ER stress and apoptosis in the thoracic aorta were measured. Furthermore, cell proliferation, ROS and the protein expression associated with ER stress (especially CHOP) and apoptosis were assessed in human umbilical vein endothelial cells (HUVECs) incubated with SIT and PA. Compared to the SCD rats, the HFD rats had higher serum lipid levels, decreased vascular tension, increased inflammation, oxidative and ER stress, and apoptosis of endothelial cells. PA promoted ROS generation, ER stress and apoptosis, inhibited cell proliferation in HUVECs. SIT treatment obviously ameliorated apoptosis via alleviating ROS and ER stress in the thoracic aortas isolated from HFD-fed rats and PA-treated HUVECs. The results suggest that SIT improved endothelial function via promoting cell proliferation and alleviating ROS-ER stress-CHOP pathway both in vivo and in vitro.