Modifications in basal and stress-induced hypothalamic AMP-activated protein kinase (AMPK) activity in rats chronically treated with an angiotensin II receptor blocker

Abstract

5' adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor. The role of hypothalamic AMPK in response to restraint and surgical stress has not been previously investigated. It has been recently suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating metabolic pathways including the regulation of the AMPK system. This study was thus aimed to evaluate the effects of candesartan, an angiotensin II AT1 receptor blocker drug, on hypothalamic AMPK activity under basal conditions and after restraint in conscious rats or after surgical stress under general anesthesia. Male Wistar rats were treated with 5 mg/kg/day candesartan in the drinking water for 2 weeks. The hypothalamic AMPK activity was determined under basal and stress conditions, using a kinase activity assay. Chronic administration of candesartan significantly increased hypothalamic AMPK activity. Hypothalamic AMPK activity was also increased by restraint stress whereas no change was observed during surgical stress under anesthesia. The high levels of hypothalamic AMPK activation observed in candesartan-treated rats were not changed by restraint stress but were reduced to control levels by anesthesia and surgery. In conclusion, chronic candesartan treatment and restraint stress in conscious rats stimulate the hypothalamic AMPK activity, whereas surgical stress under anesthesia inhibits pathways regulating the AMPK activity even in candesartan-treated rats.

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…Also, metformin, a potent AMPK activator, prevented AT 1 R upregulation. These results suggest a negative reciprocal relation between AMPK and AT 1 R and are consistent with previous observations showing that the ARBs telmisartan and candesartan stimulate AMPK activity in cultured myotubes (128) and rat hypothalami (269).…”

Acute stress diminishes M-current contributing to elevated activity of hypothalamic-pituitary-adrenal axis

“…Furthermore, epithelial Na + channel membrane expression is reduced by activation of AMPK through the AMPK-Nedd4-2 pathway in Xenopus oocytes (Bhalla et al, 2006). Consistent with previous findings that acute stress increases hypothalamic AMPK activity (Marques et al, 2012), acute stress profoundly increased phosphorylated AMPK expression levels, although the total AMPK expression level was unchanged. We also found that inhibition of AMPK activity with its specific inhibitor restored acute stress-induced reduction of membrane Kv7.3 expression in the PVN tissue and recovered the decreased M-currents in the PVN-CRH neurons induced by stress.…”

“…AMPK is involved in many cellular processes, such as regulation of apoptosis, stimulation of autophagy and phagocytosis, inhibition of cell growth and proliferation, and counteraction of hypertrophy (Dermaku-Sopjani et al, 2014; Hardie, 2003). Acute restraint stress increases AMPK activity (Marques et al, 2012) and AMPK activation in the central nervous system mediates fructose-induced elevation of plasma corticosterone (CORT) levels (Kinote et al, 2012). Furthermore, AMPK activation decreases membrane expression of Kv7.1 and epithelial Na + channel through promoting endocytosis and degradation in lysosomes via a Nedd2-4-dependent mechanism (Andersen et al, 2012; Bhalla et al, 2006).…”

Adipose Tissue-Specialized Immunologic Features Might Be the Potential Therapeutic Target of Prospective Medicines for Obesity

“…AMPK in the hypothalamus is a common regulator of weight gain. As a stress sensor, AMPK can be activated by a cluster of factors such as oxidative, metabolic, and physical stresses [39, 41, 42]. According to the heterotrimeric complex with one catalytic α subunit and two regulatory units β and γ , AMPK contains two isoforms of α ( α 1 and α 2) and β ( β 1 and β 2) with three γ subunits ( γ 1, γ 2, and γ 3).…”