Preliminary Adipose Removal Did Not Prevent Diet-Induced Metabolic Disorders in Mice
Obesity is a significant risk factor for metabolic disorders such as hyperlipidemia, insulin resistance, fatty liver, and atherosclerosis. Despite its prevalence, effective preventive measures remain limited. This study aimed to explore whether surgical removal of adipose tissue before the onset of obesity could prevent diet-induced metabolic disorders in low-density lipoprotein receptor (LDL-R) knockout (KO) mice, a model commonly used in lipid and cardiovascular research.
The study involved male LDL-R KO mice aged 5 to 6 months, which were randomly divided into four groups: sham-operation, epididymal fat removal (Epi-FR), subcutaneous fat removal (suQ-FR), and combined epididymal and subcutaneous fat removal (Epi + suQ-FR). After a one-week recovery period, all mice were fed a high-fat diet (HFD) containing 20% fat and 0.5% cholesterol for 10 weeks to induce metabolic disorders. Body weight was monitored every two weeks, and at the end of the study, various metabolic parameters were assessed, including plasma lipid and glucose levels, insulin sensitivity, liver lipid content, and atherosclerotic burden.
The results showed that preliminary adipose removal did not significantly alter the weight gain of the mice compared to the sham-operated group. In the Epi-FR group, the residual subcutaneous fat increased to 28.59 mg/g, compared to 18.56 mg/g in the sham-operated group. Gene expression analysis revealed that genes related to adipogenesis (Pparg, Cebpa), lipogenesis (Dgat2), and lipid transport (Fabp4, Cd36) were upregulated in the residual subcutaneous fat of the Epi-FR group. However, no significant changes in gene expression were observed in the other fat-removal groups.
Plasma lipid levels, including total cholesterol (TC), triglycerides (TGs), and high-density lipoprotein cholesterol (HDL-C), were measured at various time points during the HFD feeding. The results indicated that adipose removal did not significantly alleviate hyperlipidemia. Similarly, glucose tolerance tests (GTT) showed no improvement in insulin sensitivity in the fat-removal groups compared to the sham-operated group. Hepatic lipid content, as assessed by Oil Red O staining and direct measurement of TG and TC levels, also did not show significant attenuation in any of the fat-removal groups.
Atherosclerotic burden was evaluated by Oil Red O staining of the entire aorta and aortic root sections. The results demonstrated that adipose removal did not reduce the atherosclerotic plaque burden in the aorta or aortic root. These findings suggest that preliminary removal of epididymal or subcutaneous adipose tissue, either alone or in combination, does not protect against diet-induced metabolic disorders in LDL-R KO mice.
The study also explored the compensatory responses of residual adipose tissue after partial removal. Hematoxylin and eosin (HE) staining showed no significant difference in adipocyte size between the fat-removal groups and the sham-operated group. Gene expression analysis indicated that while certain genes were upregulated in the residual subcutaneous fat of the Epi-FR group, no significant changes were observed in the epididymal fat of the suQ-FR group. This suggests that partial adipose removal does not lead to significant compensatory responses in the residual fat depots.
The findings of this study are consistent with previous research showing that surgical removal of adipose tissue in obese subjects can improve metabolic disorders. However, this study uniquely focuses on the preventive potential of adipose removal before the onset of obesity. The use of LDL-R KO mice, which are naturally hypercholesteremic and atherosclerosis-prone, provides a more relevant model for studying human metabolic disorders.
One possible explanation for the lack of protective effects observed in this study is that the functions of residual white and brown adipose tissues, such as the secretion of adipokines (e.g., adiponectin, leptin, resistin) and thermogenesis, may compensate for the removed adipose tissue. Although the mass, histology, and gene expression of the residual adipose tissues did not show significant changes, it is possible that their functional adaptations were sufficient to maintain metabolic homeostasis. Alternatively, the protective effects of adipose removal, if any, may be too weak to be detected under the strong metabolic stress induced by the HFD.
The study also highlights the limitations of using surgical adipose removal as a preventive measure for metabolic disorders. While previous studies have shown that adipose removal can improve metabolic parameters in obese subjects, this study demonstrates that such interventions may not be effective in preventing the onset of metabolic disorders in individuals susceptible to obesity. This suggests that other strategies, such as dietary modifications, exercise, or pharmacological interventions, may be more effective in preventing obesity-related metabolic disorders.
In conclusion, this study provides comprehensive evidence that preliminary removal of epididymal or subcutaneous adipose tissue, either alone or in combination, does not protect against diet-induced metabolic disorders in LDL-R KO mice. These findings suggest that adipose removal may not represent a viable approach for preventing obesity-related metabolic disorders in the obesity-susceptible population. Further research is needed to explore alternative strategies for preventing metabolic disorders and to better understand the compensatory mechanisms of residual adipose tissue following partial removal.
doi.org/10.1097/CM9.0000000000001334
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