Abstract
Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks. BARD was administered daily in drinking water. Interscapular BAT, and ventrolateral medulla (VLM) and dorsal vagal complex (DVC) in the brainstem, were collected for analysis by histology, immunohistochemistry and Western blot. BARD prevented fat deposition in BAT, demonstrated by the decreased accumulation of lipid droplets. When administered BARD, HFD mice had lower numbers of F4/80 and CD11c macrophages in the BAT with an increased proportion of CD206 macrophages, suggesting an anti-inflammatory effect. BARD increased phosphorylation of tyrosine hydroxylase in BAT and VLM. In the VLM, BARD increased energy expenditure proteins, including beta 3-adrenergic receptor (β3-AR) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Overall, oral BARD prevented fat deposition and inflammation in BAT, and stimulated sympathetic nerve activity.
Highlights
Obesity is associated with serious health effects, such as type 2 diabetes and heart disease.Obesity affects the health of various tissues in the periphery and the brain [1,2,3]
Animals were divided into three groups (n = 7), and fed either a high-fat diet (HFD), a high-fat diet supplemented with bardoxolone methyl (HFD/Bardoxolone methyl (BARD)), or a low-fat diet (LFD)
Studies have demonstrated the preventative effects of BARD on obesity and obesity-associated complications [31,34]
Summary
Obesity affects the health of various tissues in the periphery (i.e., white and brown adipose tissue) and the brain [1,2,3]. Brown adipose tissue (BAT) is the primary site for non-shivering thermogenesis and energy expenditure. In contrast to white adipose tissue (WAT) which stores energy, BAT dissipates energy from food as heat, leading to a reduction in fat storage and weight gain [4]. BAT is present in human adults [5,6], and has been extensively investigated as a therapeutic target to prevent and treat obesity. BAT is higly innervated by sympathetic nerves and the brainstem is an autonomic center for sympathetic outflow to this tissue [7]. The noradrenergic nucleus in the brainstem contains sympathetic nerves which releases norepinephrine and innervates tissues, including BAT. A reduced level of TH mRNA has been found in the brainstem of olanzapine-induced overweight rats [10]
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