Abstract
BackgroundExposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus. Such hypothalamic inflammation is associated with metabolic dysfunction, central leptin resistance, and maintenance of obesity. Bariatric surgeries result in long-term stable weight loss and improved metabolic function. However, the effects of such surgical procedures on HFD-induced hypothalamic inflammation are unknown. We sought to characterize the effects of two bariatric surgical procedures, Roux-en-Y gastric bypass (RYGB) and biliary diversion (BD-IL), in female mice with particular emphasis on HFD-induced hypothalamic inflammation and microgliosis.MethodsRYGB and BD-IL were performed on diet-induced obese (DIO) mice. Quantitative RT-PCR and fluorescent microscopy were used to evaluate hypothalamic inflammatory gene expression and microgliosis. Results were compared to lean (CD), DIO sham-surgerized mice (DIO-SHAM), and dietary weight loss (DIO-Rev) controls.ResultsIn female mice, RYGB and BD-IL result in normalization of hypothalamic inflammatory gene expression and microgliosis within 8 weeks of surgery, despite ongoing exposure to HFD. Paralleling these results, the hypothalamic expression levels of the orexigenic neuropeptide Agrp and the anorexic response of surgical mice to exogenous leptin were comparable to lean controls (CD). In contrast, results from DIO-Rev mice were comparable to DIO-SHAM mice, despite transition back to standard rodent show and normalization of weight.ConclusionBariatric surgery attenuates HFD-induced hypothalamic inflammation and microgliosis and restores leptin sensitivity, despite ongoing exposure to HFD.
Highlights
Exposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus
To evaluate the ability of these procedures to ameliorate metabolic parameters in female mice, we compared surgical mice to diet-induced obesity (DIO) sham-surgerized (DIO-SHAM) and lean controls (CD), as well as DIO mice transitioned from high-fat diet to standard chow diet (DIO-Rev) (Fig. 1a)
Biliary diversion to the ileum (BD-IL) and Roux-en-Y gastric bypass (RYGB) bariatric surgeries normalize HFDinduced hypothalamic metaflammation Given the improvement in microgliosis, we evaluated hypothalamic proinflammatory gene expression in wild-type C57BL/6J mice following bariatric surgery
Summary
Exposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus. We sought to characterize the effects of two bariatric surgical procedures, Roux-en-Y gastric bypass (RYGB) and biliary diversion (BD-IL), in female mice with particular emphasis on HFD-induced hypothalamic inflammation and microgliosis It is well established, in human and rodent models, that caloric excess and the ensuing diet-induced obesity (DIO), result in a state of chronic, low-grade inflammation and accumulation of professional immune cells such as macrophages in metabolic tissues including liver, adipose and muscle. Hypothalamic metaflammation and microglial activation contribute to hypothalamic resistance to peripheral anorexic hormones such as leptin, increasing the threshold for leptin’s catabolic effects and contributing to an elevated level of homeostatically defended body weight (Zhang et al 2008) Both pharmacologic and genetic experimental interventions that inhibit hypothalamic inflammatory pathways reduce food intake and body weight and improve the response of obese animals to exogenous leptin (Zhang et al 2008). Given the known effects of hypothalamic metaflammation on hypothalamic leptin resistance, these studies raise the possibility that bariatric surgery may improve hypothalamic metaflammation contributing to a lower set point of defended body weight
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