Acute and repeated restraint differentially activate orexigenic pathways in the rat hypothalamus

Abstract

Stress and obesity are highly prevalent conditions, and the mechanisms through which stress affects food intake are complex. In the present study, stress-induced activation in neuropeptide systems controlling ingestive behavior was determined. Adult male rats were exposed to acute (30 min/d × 1 d) or repeated (30 min/d × 14 d) restraint stress, followed by transcardial perfusion 2h after the termination of the stress exposure. Brain tissues were harvested, and 30 µm sections through the hypothalamus were immunohistochemically stained for Fos protein, which was then co-localized within neurons staining positively for the type 4 melanocortin receptor (MC4R), the glucagon-like peptide-1 receptor (GLP1R), or agouti-related peptide (AgRP). Cell counts were performed in the paraventricular (PVH), arcuate (ARC) and ventromedial (VMH) hypothalamic nuclei and in the lateral hypothalamic area (LHA). Fos was significantly increased in all regions except the VMH in acutely stressed rats, and habituated with repeated stress exposure, consistent with previous studies. In the ARC, repeated stress reduced MC4R cell activation while acute restraint decreased activation in GLP1R neurons. Both patterns of stress exposure reduced the number of AgRP-expressing cells that also expressed Fos in the ARC. Acute stress decreased Fos-GLP1R expression in the LHA, while repeated restraint increased the number of Fos-AgRP neurons in this region. The overall profile of orexigenic signaling in the brain is thus enhanced by acute and repeated restraint stress, with repeated stress leading to further increases in signaling, in a region-specific manner. Stress-induced modifications to feeding behavior appear to depend on both the duration of stress exposure and regional activation in the brain. These results suggest that food intake may be increased as a consequence of stress, and may play a role in obesity and other stress-associated metabolic disorders.

Food-intake regulation during stress by the hypothalamo-pituitary-adrenal axis

“…Although GC administration stimulates both orexigenic neuropeptides (see earlier), but during stressful events their expressions are differentially regulated (Kas et al, 2005). More precisely, acute and repeated restraint reduces the number of AgRP-expressing cells (Chagra et al, 2011), and brief session of inescapable foot shocks down-regulates AgRP mRNA levels in ARC in the rat hypothalamus (Kas et al, 2005). AgRP is known to be the natural antagonist for the type 4 melanocortin (MC-4) receptors mediating anorexigenic signals of melanocortins (Leibowitz and Wortley, 2004).…”

“…Food intake Anorexia (Bazhan et al, 2007;De Souza et al, 2000;Fryer et al, 1997;Harris et al, 2001;Krahn et al, 1990;Rybkin et al, 1997) Hyperphagia (Dallman, 2010;Dallman et al, 2005;Foster et al, 2009;la Fleur et al, 2005;Pecoraro et al, 2004) Mechanisms Stress induces anorexia due to decreased signaling of: AgRP (Chagra et al, 2011;Kas et al, 2005) NPY (Tempel and Leibowitz, 1994;White, 1993) due to increased signaling of: insulin? (Chavez et al, 1997;Warne, 2009) leptin?…”

Stress induced obesity: lessons from rodent models of stress

“…Restraint stress is regarded as a form of mild stress, as indicated by physiologic and neuroendocrine responses, however, it has been shown to increase expression of orexigenic peptides in the hypothalamus nonetheless (Chagra et al, 2011). Interestingly, the expression of orexigenic peptides seems to increase when restraint stress is repeated over time (Chagra et al, 2011) and it has been shown that feeding responses to restraint stress are maintained in the absence of the stressor (Tamashiro et al, 2007a). Mild restraint stress has the ability to increase the number of AgRP-expressing neurons, while simultaneously reducing α-MSH receptors, in the ARC (Chagra et al, 2011).…”

A tale of two circuits: CCK NTS neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions

“…Following a meal, CCK NTS neurons become activated and relay visceral input from the vagus to brain regions known to mediate changes in feeding (Rinaman, 2010). Interestingly, the same brain regions that are important for feeding behavior have also been shown to influence behavioral responses to emotionally relevant stimuli associated with fear, stress, and pain (Bernard and Besson, 1990; Bester et al, 2000; Casada and Dafny, 1992; Chagra et al, 2011; Han et al, 2015; LeDoux, 2000). Two such regions receiving especially dense innervation from CCK NTS neurons are the PBN and PVH.…”