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Objective The mechanism for different susceptibilities to obesity after short-term high-fat diet (HFD) feeding is largely unknown. Given the close association between obesity occurrence and mitochondrial dysfunction, the early events in skeletal muscle mitochondrial adaptations between HFD-induced obesity (DIO) and HFD-induced obesity resistant (DIO-R) lean phenotype under excess nutritional environment were explored. Methods ICR/JCL male mice were randomly divided into 2 groups, as follows: low-fat diet (LFD) and HFD groups. After 6 weeks on HFD, HFD-fed mice were classified as DIO or DIO-R according to their body weight gain. Serum parameters, oxidative stress biomarkers, the activation of AMPK/ACC axis, and the expression profiles of mitochondrial biogenesis were measured by using corresponding methods among the LFD control, DIO, and DIO-R groups. Results Serum glucose, total cholesterol, low-density lipoprotein, and high-density lipoprotein levels were significantly increased in DIO and DIO-R mice compared with LFD controls. However, DIO-R mice had significantly higher MDA levels and exhibited a significantly higher level of AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inactivation than DIO mice. Furthermore, the transcript and protein levels of transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) and estrogen-related receptor-α (ERRα) in DIO-R mice were significantly up-regulated compared with the DIO mice. Conclusions Although the body weight gain differed, the DIO and DIO-R mice had similar metabolic disturbance of glucose and lipids after short-term HFD consumption. The diverse alterations on fatty acid oxidation and mitochondrial biogenesis pathway induced by AMPK activation might be involved in different susceptibilities to obesity when consuming HFD. [ABSTRACT FROM AUTHOR]

Background: In this study, we investigated whether Smad4 signaling is involved in the regulation of beta-cell function using a high fat diet (HFD)-induced obesity mouse model. Methods: Beta-cell-specific Smad4-knockout mice (Smad4-/-RIP-Cre+; β-Smad4KO) were generated by mating Smad4 (flox/flox) mice with rat insulin promoter (RIP)-Cre mice. Mice were fed a HFD beginning at 6 weeks of age for 16 weeks. Body weight, food intake, fasting and fed glucose levels, and glucose and insulin tolerance were measured. Results: The expression of Smad4 mRNA was significantly decreased in the islets of β-Smad4KO mice. In wild-type mice, Smad4 mRNA was significantly decreased at 18 weeks of age as compared with 8 weeks of age. On a regular chow diet, β-Smad4KO mice showed no differences in body weight, fed and fasting blood glucose levels, and glucose tolerance compared with wildtype mice. When fed a HFD, body weight gain was significantly reduced in β-Smad4KO mice as compared with wild-type mice, although the amount of food intake was not different. During the HFD, fed and fasting blood glucose levels, glucose stimulated insulin secretion, disposition index and glucose tolerance were significantly improved in β-Smad4KO mice as compared with wild-type mice. However, insulin tolerance tests showed no differences between the 2 groups. Conclusion: Inhibition of Smad4 in beta-cells conferred mild but significant improvements in glucose levels and glucose tolerance in HFD-induced obese mice. Therefore, regulation of Smad4 expression may be one of the mechanisms regulating physiological expansion of beta-cells during development of type 2 diabetes. [ABSTRACT FROM AUTHOR]