Adipocyte glucocorticoid receptors mediate fat-to-brain signaling
Introduction
Stressors mobilize energy reserves to ensure survival under energetically demanding conditions of real or perceived adversity (de Kloet et al., 2005, Ulrich-Lai and Herman, 2009). As would then be expected, there is an intricate relationship between the systems that regulate metabolism and the systems that are stimulated in response to stress. Activation of the hypothalamic–pituitary–adrenal (HPA) axis is a primary component of the metabolic stress response, culminating in the secretion of glucocorticoids (corticosterone in mice; cortisol in humans) and consequent redistribution of fuel sources (mobilization of hepatic glucose production, enhanced adipocyte differentiation). The interrelated contribution of the HPA axis to stress and metabolism is reflected in the link between excess glucocorticoids and visceral adiposity (e.g., Cushing's disease) (Masuzaki et al., 2001, Pasquali et al., 2006), and by evidence for pathological HPA axis activity in psychiatric pathologies such as depression (Holsboer, 2000) as well as in metabolic disorders such as diabetes and obesity (Masuzaki et al., 2001, Pasquali et al., 2006, Rosmond et al., 1998). Furthermore, obesity predisposes individuals to develop depression (Roberts et al., 2003, Simon et al., 2006).
Stress activation of the HPA axis is controlled by negative feedback mechanisms, whereby glucocorticoids bind to cognate receptors to inhibit further release of ACTH. There are two known receptors for glucocorticoids, the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The MR has high affinity for glucocorticoids and is extensively bound under resting conditions, even at the nadir of the circadian rhythm (De Kloet et al., 1998). In contrast, the GR is only extensively occupied at high circulating glucocorticoid levels, and is the major mediator of negative feedback (Myers et al., 2012). In recent years it has become apparent that feedback can be mediated by multiple mechanisms. For example, fast feedback shut-off of CRH neurons is mediated by non-genomic, membrane glucocorticoid signaling, probably mediated by the GR (Evanson et al., 2010). Additional regions are also involved in feedback inhibition, including the hippocampus, medial prefrontal cortex and even nucleus of the solitary tract neurons in the hindbrain (Ghosal et al., 2014, McKlveen et al., 2013, Myers et al., 2012). Consequently, regulation of stress responses is a distributed process involving multiple brain mechanisms.
Although the inter-relationship between stress-responding and metabolism is documented, the underlying mechanism(s) connecting the systems that regulate energy storage and those that regulate the HPA axis are not clear. There is extensive overlap between the brain mechanisms regulating stress responses and those that influence metabolism and this is likely further complicated by peripheral factors. In this regard, it has been hypothesized that a factor within adipose tissue plays an important role in mediating the interactions by coordinately regulating energy storage and HPA-axis stress responsiveness (Dallman et al., 2003b, Laugero et al., 2001). Consistent with this hypothesis, the ingestion of comfort foods during stress exposure suppresses HPA axis activity by stimulating reward circuitry in the brain (Ulrich-Lai et al., 2010), while the redistribution of adiposity toward increased visceral stores contributes to the attenuation of HPA responding (Dallman et al., 2003b, Laugero et al., 2001, Pecoraro et al., 2004).
While it is accepted that glucocorticoids inhibit their own secretion via the activation of GR within specific brain regions and in the pituitary, the existence of peripheral populations of GR in tissues such as white adipose tissue raises the possibility of reciprocal body-to-brain feedback signals that link metabolic and neural processing in the regulation of key stress responses. The present studies are based on the realization that GR is highly expressed in adipocytes and therefore is in an ideal position to mediate the interactions between stress and metabolism. To assess this possibility, we investigated the role of adipocyte glucocorticoid signaling in energy metabolism and HPA axis activity using mice with selective knockdown of the GR in fat cells. We demonstrate that direct action of glucocorticoids on GR within adipocytes is an important mechanism for both HPA axis and metabolic regulation. This pathway may represent an important link between obesity and psychopathology.
Section snippets
Animals
Mice containing the GR flox allele (Brewer et al., 2003) were crossed with mice containing Cre recombinase under control of the adiponectin promoter (Wang et al., 2010) to generate mice (C57BL/6 × 129 background) with reduced GR in adipocytes. Adult male and female adipocyte-GR knock-down mice (KO) and littermate controls expressing only the adiponectin Cre transgene (and for an additional control experiment containing only the GRflox allele [i.e., no adiponectin Cre transgene]) were housed one
Specific Cre/lox-mediated deletion of the glucocorticoid receptor from adipocytes
For these studies, Cre-recombinase was expressed under the control of the promoter for adiponectin, a molecule expressed exclusively in adipocytes (Hu et al., 1996, Scherer et al., 1995). Expression of this adiponectin-Cre transgene (Wang et al., 2010) in knock-in mice homozygous for a loxP-flanked GR exon 2 (Brewer et al., 2003) leads to a significant reduction in GR protein in eWAT [t(8) = 3.23, p < 0.05], with no off-target reduction in GR expression within the hypothalamus, pituitary, adrenal
Discussion
The HPA axis is regulated by a complexity of neuroendocrine and autonomic signals, and perturbations of HPA axis function contribute to a wide range of psychiatric and metabolic diseases (de Kloet et al., 2006, Holsboer, 2000, Pasquali et al., 2006, Rosmond et al., 1998). Previous studies document glucocorticoid regulation of HPA axis activity at the hypothalamic, pituitary and adrenal levels. However, it has been hypothesized that other populations of GR also regulate activity of the HPA axis (
Role of the funding source
The present studies were funded by NIH grants, MH069860, MH049698, HL096830 and NS068122. The funding source had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Conflict of interest
None declared.
Acknowledgments
The authors would like to thank Drs. Scherer and Muglia for the donation of the Adiponectin Cre and GR flox mouse lines.
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2019, Molecular Aspects of MedicineCitation Excerpt :In these mice, the GR is functionally knocked-out in mature brown and white adipocytes, but is still present in the adipose tissue stromal-vascular fractions containing preadipocytes. Knocking-out the GR in this adipose-tissue specific manner may attenuate the development of obesity as well as the accumulation of WAT mass in response to high-fat diet feeding and aging, but these results are controversial (Bose et al., 2016; de Kloet et al., 2015; Desarzens and Faresse, 2016; Mueller et al., 2017; Shen et al., 2017). Concerning BAT, there seems to be little difference between adiposeGR-KO and wild-type mice.