Central Administration of an Endoplasmic Reticulum Stress Inducer Inhibits the Anorexigenic Effects of Leptin and Insulin

Abstract

Leptin and insulin are important anorexigenic hormones acting on the hypothalamus. However, most obese humans and animals have reduced hypothalamic responses to leptin and insulin. Increased endoplasmic reticulum (ER) stress has been shown to cause insulin resistance in the livers of obese animals. In the present study, we investigated a role of ER stress in the development of central leptin and insulin resistance. Intracerebroventricular (ICV) administration of the ER stress inducer thapsigargin (TG) increased food intake and body weight. Furthermore, ICV or intra‐hypothalamic administration of TG inhibited the anorexigenic and weight‐reducing effects of leptin and insulin. ICV administration of TG by itself activated signal‐transduction‐activated‐transcript‐3 (STAT3) and Akt in the hypothalamus, but prevented a further activation of hypothalamic STAT3 and Akt by leptin and insulin. We also found that the expression of the ER stress markers such as phosphorylation of the inositol‐requiring kinase‐1 (IRE1), spliced form of X‐box‐binding protein‐1 (XBP‐1s), glucose‐regulated/binding immunoglobulin protein‐78, and C/EBP homology protein (CHOP) increased in the hypothalami of diet‐induced obese (DIO) mice. Furthermore, treatment of chemical chaperone 4‐phenyl butylic acid significantly improved central leptin resistance in DIO mice. These findings suggest that increased hypothalamic ER stress in obese animals may induce central leptin and insulin resistance.

Ghrelin and lipid metabolism: key partners in energy balance

“…As stated earlier, to avert a harmful drop in the levels of malonyl-CoA in the hypothalamus, data have shown that a physiological adaptive mechanism causes ghrelin-and fasting-induced decreases in FAS levels in the VMH (Andrews et al 2008. Since this regulatory mechanism is lost in dwarf rats, it is possible that an accumulation of toxic lipid species and lipotoxicity-associated phenomena, such as ER stress (Hosoi et al 2008, Zhang et al 2008, Ozcan et al 2009, Won et al 2009, Martínez de Morentin et al 2010b, might be caused by altered fatty acid fluxes in the hypothalamic neurons, which may be induced from GH-deficiency, thus hindering hypothalamic metabolism in these animals. Further work will be necessary to address these issues.…”

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

“…An elevation in plasma leptin levels is also anorexigenic (Ortolani et al, 2011;Won et al, 2009;Zareian et al, 2011). GCs can interact with leptin in the long-term regulation of energy intake and body adiposity.…”

Loss of Stearoyl-CoA Desaturase-1 Activity Induced Leptin Resistance in Neuronal Cells

“…29) ER stress also plays a key role in the pathophysiology of leptin resistance. [14][15][16] The activation of unfolded protein response (UPR) by membrane lipid saturation mediates different mechanism from those activated by ER stress. 30) In the presence of unfolded or misfolded proteins in the ER, cells activates an adaptive response UPR by sensing a luminal stress signals to activate the luminal stress-sensing domain of the UPR-related proteins, inositol-requiring enzyme 1α (IRE1α) and protein kinase Rlike endoplasmic reticulum-resident kinase (PERK).…”

“…12) Lipotoxicity is associated with endoplasmic reticulum (ER) stress, 13) one of the mechanisms of the pathogenesis of leptin resistance. [14][15][16] Exogenous fatty acids from the diet influence the fatty acid composition of the membrane phospholipids.…”