Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4

Abstract

ObjectiveGlucagon-like peptide-1 (GLP-1) analogs are attractive options for the treatment of type II diabetes and obesity because of their incretin and anorexigenic effects. Peripheral administration of the GLP-1R agonist Exendin-4 (Ex-4) also increases glucocorticoid secretion in rodents and humans, but whether the released glucocorticoids interact with Ex-4's anorexigenic effect remains unclear.MethodsTo test this, we used two experimental approaches that suppress corticosterone secretion and then assessed Ex-4 effects on eating in adult male rats. First, we combined acute and chronic low dose dexamethasone treatment with Ex-4. Second, we ablated hindbrain catecholamine neurons projecting to the hypothalamus with anti-dopamine-β-hydroxylase-saporin (DSAP) to block Ex-4-induced corticosterone secretion.ResultsCombining dexamethasone and Ex-4 produced a larger acute anorexigenic effect than Ex-4 alone. Likewise, chronic dexamethasone and Ex-4 co-treatment produced a synergistic effect on eating and greater body weight loss in diet-induced obese rats than Ex-4 alone. DSAP lesions not only blunted Ex-4's ability to increase corticosterone secretion, but potentiated the anorexigenic effect of Ex-4, indicating that Ex-4-dependent corticosterone secretion opposes Ex-4's actions. Consistent with the enhancement of Ex-4's anorexigenic effect, DSAP lesion altered Ex-4-dependent changes in neuropeptide Y, preproglucagon, and corticotropin releasing hormone gene expression involved in glucocorticoid feedback.ConclusionsOur findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies.

Central noradrenaline transporter availability in highly obese, non-depressed individuals

“…This might be due to technical reasons (i.e. the different scanners used in each study), that is high-resolution research tomography (HRRT) vs. ECAT EXACT HR+ or different radioactivities [(596 MBq [6]) and low (359 MBq, this investigation)] of [ 11 C]MRB administered. Thus, time-activity curves were marginally less noisy from injections of high radioactivity compared to those with low radioactivity; however, the outcome measures with high radioactivity were not evidently improved in a study in rhesus monkeys (albeit both amounts of radioactivity were high translated into humans) [23].…”

“…It has been shown in rats that NA acting in the hypothalamic arcuate, ventromedial and paraventricular nuclei stimulates feeding [3–5], whereas it inhibits feeding in the lateral hypothalamic area [3] through α- and β-receptors. Furthermore, ablating hindbrain noradrenergic neurons which project to the hypothalamic arcuate and paraventricular nuclei eliminates orexigenic [5] and potentiates anorexigenic [6] actions of feeding hormones in rats, respectively. Also, electrically silencing NA neurons of the locus coeruleus (LC) reduces brown adipose tissue thermogenesis leading to obesity in mice through reduced energy expenditure [7].…”

Catecholaminergic projections into an interconnected forebrain network control the sensitivity of male rats to diet-induced obesity

“…A1 and C1 VLM neurons are intimately involved with driving rapid responses to physiological challenges (17,18,49,53). In this way, these hindbrain catecholaminergic projections collectively mediate a broad range of feeding and adrenal counterregulatory responses to hypoglycemia, cytoglucopenia, cholecystokinin, and glucagonlike peptide 1 (GLP-1) receptor stimulation (12,21,25,26,30,46,47,50).…”

Neurotransmitter diversity in pre‐synaptic terminals located in the parvicellular neuroendocrine paraventricular nucleus of the rat and mouse hypothalamus

“…Catecholaminergic afferents provide stimulus‐specific information to the PVHmpd, particularly for acute physiological challenges (Ritter, Li, Wang, & Dinh, ; Guyenet et al, ). These neurons are indispensable for glucocorticoid responses to insulin‐induced hypoglycemia, and are major contributors for responses to 2‐deoxy‐ d ‐glucose (2DG) or GLP‐1 agonists (Ritter, Bugarith, & Dinh, ; Ritter, Watts, Dinh, Sanchez‐Watts, & Pedrow, ; Khan et al, ; Lee et al, ). They are also required to maintain the sensitivity of CRH mRNA to elevated levels of corticosterone (Kaminski & Watts, ) and to gate metaplasticity at GABA inputs on CRH neurons following an acute stress (Inoue et al, ).…”

“…Catecholaminergic afferents provide stimulus-specific information to the PVHmpd, particularly for acute physiological challenges (Ritter, Li, Wang, & Dinh, 2011;Guyenet et al, 2013). These neurons are indispensable for glucocorticoid responses to insulin-induced hypoglycemia, and are major contributors for responses to 2-deoxy-D-glucose (2DG) or GLP-1 agonists (Ritter, Bugarith, & Dinh, 2001;Ritter, Watts, Dinh, Sanchez-Watts, & Pedrow, 2003;Khan et al, 2007;Lee et al, 2016).…”