Hypothalamic neurogenesis and its implications for obesity-induced anxiety disorders
Introduction
Obesity is a complex disorder and a major risk factor for many health complications, including diabetes, cardio and cerebrovascular diseases, osteoarthritis, cancers, as well as neurodegenerative disorders (Frasca et al., 2017). Obesity is a global problem which involves various socio-economic factors and occurs largely due to a positive caloric energy balance (Romieu et al., 2017). Additionally, obese patients often suffer with high levels of anxiety and depression (Esposito et al., 2014, Luppino et al., 2010). The mechanisms of obesity-induced anxiety behaviour is not fully understood and is simply not as a result of increasing body mass, since weight loss alone does not always account for an improvement in mental health (Canetti et al., 2016, Cunningham et al., 2012). Often adding further complexities to disease pathophysiology are sex-specific differences (Lovejoy and Sainsbury, 2009, Marques, 2016), the mechanisms of which need to be considered and more importantly understood, in the interest of precision medicine (Yagi and Galea, 2019). Currently, obesity and obesity-induced psychological disorders, have no effective cure, while therapeutic strategies are primarily aimed at lifestyle modification interventions (Montesi et al., 2016), and even these have limitations associated with low adherence.
Situated at the convergence of many neural pathways, the hypothalamus is at the centre of the limbic system (Rajmohan and Mohandas, 2007) and serves as a regulator of several critical homeostatic processes like appetite and thirst, blood pressure, reproduction and core body temperature control, circadian rhythms and sleep as well as aging (Van Someren, 2000). It also mediates whole body emotional responses through the autonomic nervous system (McCorry, 2007), with hypothalamic stimulation activating behavioural functions related to motivation and reward, with damage to this brain area having inhibitory effects in this regard (Sharpe et al., 2017). Its position at the base of the brain makes it ideally positioned to respond to fluxes in metabolite and hormonal levels in circulation, in order to modulate physiology and behaviour (Langlet, 2014).
Neurogenesis is an important mechanism conferring neuroplasticity (Ming and Song, 2011) and is crucial to the hypothalamus to continuously adapt to change in the internal and external environment. Neurogenic remodelling has largely been studied in the hippocampus (Petrik and Encinas, 2019), with several factors already being determined to affect this process, both positively and negatively (Li and Pleasure, 2010). Evidence over the last decade or so has shown that hypothalamic neurogenesis occurs to a much lesser extent, with several studies confirming this process in humans (Batailler et al., 2014, Dahiya et al., 2011). Recent work from Pellegrino and colleagues in 2018, showed that adult humans contain four-distinct populations of cells that express neuronal stem cell (NSCs) markers, with three of these being human-specific (Pellegrino et al., 2018). While, the mechanisms responsible for obesity-linked anxiety and depressive disorders remain largely undetermined, it is known that inflammation arising within the hypothalamus is regarded as a primary symptom in the pathogenesis of obesity and metabolic diseases. Of interest, obesity-linked inflammation is also associated with anxiety and depression, as well as cognitive impairment (Esposito et al., 2014).
Given that the hippocampus and hypothalamus are tightly and reciprocally connected (Pasquier and Reinoso-Suarez, 1976) and the fact that several pro-neurogenic therapeutic interventions have already been identified in the hippocampus, it is plausible to attempt these therapies to target the hypothalamus in the treatment of obesity. This review will describe hypothalamic neurogenesis and neuroplasticity and particularly focus on studies evaluating its impairment in dietary models of obesity. Furthermore, interventions that have thus far been successfully employed to improve these processes within the hypothalamus will be discussed.
Section snippets
The hypothalamic neurogenic niche
From the analysis of the hippocampal sub-ventricular and sub-granular zones have allowed for the characteristics of a neurogenic niche to be identified (Bjornsson et al., 2015). Befitting of this criterion, the basal hypothalamus has since emerged as a plausible candidate for a novel neurogenic niche within the adult brain (Bjornsson et al., 2015, Klein et al., 2019). Importantly, the basal hypothalamus contains a stem progenitor cell population in the form of tanycytes and associated cells
Hypothalamic neuroplasticity is dysfunctional in obesity
Given the importance of the hypothalamus in controlling energy metabolism, several studies using animal models of diet-induced obesity (DIO) and have evaluated the effects on neurogenesis (Table 1). Rodent studies using both weanlings and adult animals, have demonstrated that dietary fat can cause the dysregulation in expression of feeding related peptides within the hypothalamus, having profound effects on body weight and adiposity, leading to obesity (McNay et al., 2012). In a study examining
Pro-neurogenic interventional therapies for obesity
Obesity is a modifiable risk factor for several serious illnesses and attempts to positively modulate hypothalamic neurogenesis (Table 2) could prove to be fruitful in treating this disease. In the hippocampus, both dietary manipulation and certain nutraceuticals have been shown to be useful in promoting neurogenesis (Park and Lee, 2011, Xu et al., 2007). Resveratrol (RSV), is one such naturally occurring polyphenol known to affect body fat mass and is able to reduce adipose tissue (Kim et al.,
The hypothalamic and hippocampal connection
The anatomical hypothalamic-hippocampal connection has long been established and is functionally necessary for a global integration of various external and internal stimuli, ultimately aimed at the survival and well-being of every individual. Hypothalamic nuclei project through the fornix superior and the fimbria to the dorsal posterior hippocampus, while smaller nuclei projections act as a relay station of extrinsic afferents to the ventral hippocampus (Pasquier and Reinoso-Suarez, 1976).
Future contemplations
The most serious limitation in the study of neurogenesis remains, and that is the lack of any phenotypical biomarker to conclusively link changes observed (even in response to known pro-neurogenic stimulus as identified in animals) to an enhancement in this process in humans. This is particularly significant, since the involvement of other biologically relevant mechanism possibly contributing to the beneficial outcomes cannot be excluded (Ho et al., 2013). However, what is known for certain
Conclusion
Global obesity prevalence has escalated at an alarming rate and it still continues to do so unabated. The hypothalamus is a key brain region, where dysfunctional neurogenesis largely contributes to the development of obesity. Nutraceutical and exercise interventions can positively modulate hypothalamic neurogenesis and offers a viable treatment strategy for obesity and weight-loss management. Furthermore, the mechanisms related to obesity-induced anxiety and depressive behaviour are likely
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
This work was made possible through funding from the South African Medical Research Council’s Biomedical Research and Innovation Platform and the Division of Research Capacity Development under the SAMRC Intra-mural Postdoctoral Programme, obtained through the South African National Treasury. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders.
Ethical consideration
The authors hereby confirm that this manuscript has not been submitted, nor is currently under review by any journal. Since this is a review manuscript, not involving animals or human subjects, no ethical applications was required.
Author contributions
ES, conceptualization and produced the original draft, NC supervised, reviewed and edited, while both authors contributed to the completion of the manuscript.
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