Association of high-fat diet with neuroinflammation, anxiety-like defensive behavioral responses, and altered thermoregulatory responses in male rats.

Overweight and obesity are a worldwide pandemic affecting billions of people. These conditions have been associated with a chronic low-grade inflammatory state that is recognized as a risk factor for a range of somatic diseases as well as neurodevelopmental disorders, anxiety disorders, trauma- and stressor-related disorders, and affective disorders. We previously reported that the ingestion of a high-fat diet (HFD; 45% fat kcal/g) for nine weeks was capable of inducing obesity in rats in association with increased reactivity to stress and increased anxiety-related defensive behavior. In this study, we conducted a nine-week diet protocol to induce obesity in rats, followed by investigation of anxiety-related defensive behavioral responses using the elevated T-maze (ETM), numbers of FOS-immunoreactive cells after exposure of rats to the avoidance or escape task of the ETM, and neuroinflammatory cytokine expression in hypothalamic and amygdaloid nuclei. In addition, we investigated stress-induced cutaneous thermoregulatory responses during exposure to an open-field (OF). Here we demonstrated that nine weeks of HFD intake induced obesity, in association with increased abdominal fat pad weight, increased anxiety-related defensive behavioral responses, and increased proinflammatory cytokines in hypothalamic and amygdaloid nuclei. In addition, HFD exposure altered avoidance- or escape task-induced FOS-immunoreactivity within brain structures involved in control of neuroendocrine, autonomic, and behavioral responses to aversive stimuli, including the basolateral amygdala (BLA) and dorsomedial (DMH), paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei. Furthermore, rats exposed to HFD, relative to control diet-fed rats, responded with increased tail skin temperature at baseline and throughout exposure to an open-field apparatus. These data are consistent with the hypothesis that HFD induces neuroinflammation, alters excitability of brain nuclei controlling neuroendocrine, autonomic, and behavioral responses to stressful stimuli, and enhances stress reactivity and anxiety-like defensive behavioral responses.

Distribution of corticotropin-releasing factor binding protein-immunoreactivity in the rat hypothalamus: association with corticotropin-releasing factor-, urocortin 1- and vimentin-immunoreactive fibres.

Corticotropin-releasing factor binding protein (CRF-BP) is a 37-kDa protein with high affinity binding sites for both corticotropin-releasing factor (CRF) and urocortin 1. Previous studies have examined the distribution of CRF-BP mRNA and peptide within the central nervous system. Due to the predominant cortical localisation, very little is known about CRF-BP in subcortical structures including the hypothalamus. The present study employed immunohistochemistry to characterise the distribution of CRF-BP-like-immunoreactive (-ir) cells and fibres in the rat hypothalamus. Bipolar and multipolar CRF-BP-ir neurones were scattered throughout the rostro-caudal extent of the hypothalamus. Distinct clusters of CRF-BP-ir neurones were identified in the anterior and posterior parvocellular and dorsal cap subdivisions of the paraventricular nucleus (PVN), as well as in the dorsal hypothalamic area, dorsomedial hypothalamic nucleus (DMN), ventral premammillary nucleus and zona incerta. CRF-BP-ir fibres extending from the third ventricle were found in the mediobasal hypothalamus and within the arcuate nucleus-median eminence region. Double immunostaining together with confocal microscopy demonstrated that the CRF-BP-immunostained fibres within the mediobasal hypothalamus coincided with vimentin immunostaining indicating that CRF-BP-ir is present within tanycytes. To define the relationship between CRF-BP-ir cells and endogenous ligands for CRF-BP, double immunohistochemistry was performed to examine possible sites within the hypothalamus where CRF- or urocortin 1-ir fibres innervate regions that contain CRF-BP-ir cell bodies. CRF-BP-ir cell bodies typically coincided with dense CRF-ir, but not urocortin 1-ir fibre innervation. CRF-ir fibre innervation was moderate to high within the anterior and posterior parvocellular subdivisions of the PVN, the dorsal cap of the PVN, DMN and the zona incerta; all regions that contained CRF-BP-ir cell populations. These studies demonstrate that, within the hypothalamus, CRF-BP-ir cells and fibres are concentrated within a circuitry known to be involved in mediating neuroendocrine and autonomic responses to stress.