Abstract
High-fat diet (HFD)-induced metabolic inflammation in the central and peripheral organs contributes to the pathogenesis of obesity. Long-term HFD blunts signaling by ghrelin, a gastric-derived orexigenic peptide, in the vagal afferent nerve via a mechanism involving in situ activation of inflammation. This study was undertaken to investigate whether ghrelin resistance is associated with progressive development of metabolic inflammation. In mice, ghrelin’s orexigenic activity was abolished 2–4 weeks after the commencement of HFD (60% of energy from fat), consistent with the timing of accumulation and activation of macrophages and microglia in the nodose ganglion and hypothalamus. Calorie-restricted weight loss after 12-week HFD feeding restored ghrelin responsiveness and alleviated the upregulation of macrophage/microglia activation markers and inflammatory cytokines. HSP72, a chaperone protein, was upregulated in the hypothalamus of HFD-fed mice, potentially contributing to prevention of irreversible neuron damage. These results demonstrate that ghrelin resistance is reversible following reversal of the HFD-induced inflammation and obesity phenotypes.
Highlights
Obesity is a long-term disturbance of energy metabolism in which energy intake exceeds energy expenditure over a prolonged period (Moehlecke et al 2016)
Average food intake of HFDfed mice was lower than that of chow diet (CD)-fed mice from 2 to 12 weeks (Fig. 1B), the energy intake of HFDfed mice was greater during this period (Fig. 1C)
Two-week High-fat diet (HFD) feeding did not modulate the expression of any of the genes investigated in the nodose ganglion or hypothalamus, in comparison with 2-week CD feeding, whereas 4-week HFD feeding significantly upregulated the Iba1, Il6 and Tnfα mRNAs in comparison with 4-week CD feeding (Fig. 3D and E)
Summary
Obesity is a long-term disturbance of energy metabolism in which energy intake exceeds energy expenditure over a prolonged period (Moehlecke et al 2016). The control of food intake and body weight involves central nervous system integration of information from the peripheral nervous system and humoral signals from the gastrointestinal tract (Morton et al 2006, Begg & Woods 2013). Vagal afferents that innervate digestive organs transmit sensory information from their endings to the nucleus of the tractus solitarius (NTS) in the medulla oblongata, terminating in distinct hypothalamic nuclei involved in feeding and energy homeostasis. The vagus afferent nerve is a pseudounipolar neuron whose cell body is located in the nodose ganglion, making one projection to the NTS and the other to peripheral organs. Vagal afferent neurons express receptors for gut peptides such as ghrelin, cholecystokinin and glucagon-like peptide 1 that regulate feeding and energy homeostasis (Zarbin et al 1981, Burdyga et al 2006, Cummings & Overduin 2007).
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