Cell and molecular mechanisms behind diet‐induced hypothalamic inflammation and obesity

Abstract

Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus, a key regulator of energy homeostasis. Current studies have revealed the involvement of different cell types, as well as cell and molecular mechanisms, that contribute to diet-induced hypothalamic inflammation (DIHI) and DIO. Subsequent to the discovery that high-fat diet and saturated fatty acids increase the expression of hypothalamic cytokines prior to weight gain, research has focused on understanding the cellular and molecular mechanisms underlying these changes, in addition to the role of inflammation in the pathogenesis of obesity. Recent studies have proposed that the inhibition of pro-inflammatory pathways in microglia and astrocytes is sufficient to protect against DIHI and prevent obesity. In addition, impairment of intracellular and epigenetic mechanisms, such as hypothalamic autophagy and changes in the methylation pattern of certain genes, have been implicated in susceptibility to DIHI and DIO. Interestingly, a sexual dimorphism has been found during DIO in hypothalamic inflammation, glial activation and metabolic diseases, and recent data support an important role of sex steroids in DIHI. These new exciting findings uncover novel obesity pathogenic mechanisms and provide targets to develop therapeutic approaches.

Role of astroglia in diet-induced central neuroplasticity

“…Following chronic HFD exposure and the development of DIO, levels of critical circulating immunoregulatory proteins, including the proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin-6 and -1 (IL-6 and IL-1, respectively), increase (Fain 2006;Wisse 2004). Chronic adipose-associated systemic inflammation is associated with CNS neuroinflammation and with the consequent dysregulation of multiple neurocircuits, including those involved in caloric intake and energy homeostasis (Ávalos et al 2018;Belegri et al 2018;Dalvi et al 2017;Guillemot-Legris et al 2016;Li et al 2018;Purkayastha and Cai 2013;Wu et al 2014). While circulating cytokines have been shown to enter the central parenchyma through saturable transport mechanisms or via selective uptake in discrete brain regions such as the septum, emerging evidence suggests that neuroinflammation in response to HFD per se may actually appear long before the increase in circulating cytokines and the development of systemic inflammation associated with DIO (Banks and Kastin 1991;Bauer et al 2007;Gutierrez et al 1993).…”

“…While alterations in the brainstem neurocircuits that control gastrointestinal function have an obvious effect on gastric compliance, tone, motility, emptying rates and subsequently, meal size and energy homeostasis, HFD-induced astroglial modulation of hypothalamic signaling has also been observed (Ávalos et al 2018;Balland and Cowley 2017;Buckman et al 2015;Chowen et al 2013;Douglass et al 2017;Pfuhlmann et al 2018). Given the critical role of the hypothalamus, especially the tuberal region, in controlling appetite, modulation of these circuits may have profound effects on feeding behaviors, caloric intake, and the development of obesity (King 2005;Velloso et al 2008).…”

“…Interestingly, prolonged HFD exposure and diet-induced obesity (DIO) are associated with not only dysregulation of autonomic and metabolic functions related to energy homeostasis (Chaar et al 2016; Kentish et al 2016;Little and Feinle-Bisset 2011;Little et al 2007;McMenamin et al 2018;Troy et al 2016), but also the disruption of higher order functions such as learning, memory, mood, reward processes, and hippocampal activity (Cano et al 2014;Hao et al 2016;Spencer et al 2017;Wu et al 2018). One common thread between DIO and its wide range of comorbid disorders is the inflammation associated with increased adiposity (Ávalos et al 2018;Belegri et al 2018;Dalvi et al 2017;Guillemot-Legris et al 2016;Spencer et al 2017). Whether inflammation plays a significant role in the development of obesity, however, appears to be a more challenging and unanswered question-one that is rapidly becoming an area of great interest.…”

“…DIO has a strong association with systemic inflammation, which has been assumed to lead to the development of neuroinflammation and the dysregulation of autonomic and metabolic functions (Ávalos et al 2018;Bastard et al 2006;Belegri et al 2018;Purkayastha and Cai 2013;Tilg and Moschen 2006;Trayhurn 2005). Several groups have demonstrated recently, however, that neuroinflammation is detectable in central regions responsible for the regulation of food intake and energy homeostasis after only 1 day of HFD exposure, long before systemic inflammation is detected (Belegri et al 2018;Waise et al 2015), and well in advance of dysregulation of brainstem and hypothalamic neurocircuits (Astiz et al 2017;Belegri et al 2018, Buckman et al 2015Clyburn et al 2018).…”

Neuroendocrine regulation of reproduction, stress, inflammation and energy homeostasis

“…The cellular pathways mediating rapid glucocorticoid signalling in negative feedback effects are also discussed. The effects of steroids and endocrine disruptors during development and their long‐term consequences are extensively discussed in the review by Abruzzese et al Last but not least, the review by Avalos et al discusses the involvement of hypothalamic epigenetic mechanisms in the control of energy homeostasis and feeding behaviours.…”