Abstract
BackgroundHypothalamic obesity (HO) occurs in patients with tumors and lesions in the medial hypothalamic region. In this study, a hyperphagic rat model of combined medial hypothalamic lesions (CMHL) was used to test which specific inflammatory molecules are involved.MethodsIn order to target specific homeostatic medial hypothalamic nuclei (arcuate, ventromedial, and dorsomedial nuclei), male Sprague-Dawley rats (age of 8 weeks, ~250 g body weight) received four electrolytic lesions or sham surgery. Post-surgery food intake and weight changes were tracked and hypothalamic gene expression for inflammatory molecules as well as anorexigenic peptide oxytocin 7 days and 7 months post-surgery were tested.ResultsSeven days post-surgery, average food intake increased by 23%, and body weight gain had increased by 68%. Toll-like 4 receptor/nuclear factor–κB (TLR4/NF–κB)—pathway was specifically activated in the mediobasal hypothalamus (MBH), resulting in 3-fold higher tumor necrosis factor (TNF)-α, 10-fold higher interleukin (IL) 1-β mRNA levels, and higher expression of suppression of cytokine signaling (SOCS) 3, while oxytocin mRNA levels were significantly reduced in CMHL rats versus sham surgery rats 7 days post-surgery. At 7 months, inflammation was less stimulated in MBH of CMHL rats compared to 7 days post-surgery and SOCS 3 as well as oxytocin mRNA levels were comparable between the two groups.ConclusionMedial hypothalamic lesions are associated with strong post-surgery hyperphagia and activation of TLR4/NF–κB—pathway as well as reduced expression of oxytocin in the hypothalamus.
Highlights
Childhood obesity of any cause is a major risk factor for adult CVD and premature death [1]
Excessive weight gain frequently occurs in patients with hypothalamic tumors and lesions, a disorder designated as hypothalamic obesity (HO)
We have shown in humans and rodents that large hypothalamic tumors or lesions affecting several medial hypothalamic regions including the arcuate (ARC), ventromedial (VMN), and dorsomedial (DMN) nuclei, lead to a more severe phenotype of Hypothalamic obesity (HO) and melanocortin (MC) deficiency compared to smaller lesions and lesions of single nuclei [2,16,17,18,19,20,21,22]
Summary
Childhood obesity of any cause is a major risk factor for adult CVD and premature death [1]. Recognized risk factors for severe obesity include large hypothalamic tumors or lesions affecting several medial and posterior hypothalamic nuclei that impact satiety signaling pathways [11,12,13,14]. Structural damage in these nuclei often lead to hyperphagia, rapid weight gain, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue [2,15]. A hyperphagic rat model of combined medial hypothalamic lesions (CMHL) was used to test which specific inflammatory molecules are involved
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