Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity

Abstract

Autonomic innervation is important to regulate homeostasis in every organ of the body. The sympathetic nervous system controls several organs associated with metabolism and reproduction, including adipose tissue, the liver, and the ovaries. The sympathetic nervous system is controlled within the central nervous system by neurons located in the hypothalamus, which in turn are regulated by hormones like leptin. Leptin action in the hypothalamus leads to increased sympathetic activity in the adipose tissue. In this short report, we propose that leptin action in the brain also controls the sympathetic innervation of other organs like the liver and the ovary. We performed two experiments: We performed an intracerebroventricular (ICV) injection of leptin and measured norepinephrine levels in several organs, and we used a validated model of overnutrition and obesity to evaluate whether an increase in leptin levels coexists with high levels of norepinephrine in the liver and ovaries. Norepinephrine was measured by ELISA in adipose tissue and by HPLC-EC in other tissues. Leptin was measured by ELISA. We found that the ICV injection of leptin increases norepinephrine levels in several organs, including the liver and ovaries. Also, we found that diet-induced obesity leads to an increase in leptin levels while inducing an increase in norepinephrine levels in the liver and ovaries. Finally, since hyperactivity of the sympathetic nervous system is observed both in non-alcoholic fatty liver disease and polycystic ovary syndrome, we think that an increase in norepinephrine levels induced by hyperleptinemia could be involved in the pathogenesis of both diseases.

Keywords: fat; leptin; liver; norepinephrine; ovary; sympathetic nervous system.

Figure 1

Norepinephrine concentration in different tissues after leptin injection. (A) Norepinephrine concentration in samples obtained from different types of adipose tissue in rats after ICV injection with leptin (Experiment 1, see Section 4). From left to right: interscapular brown adipose tissue (iBAT), mesenteric white adipose tissue (mWAT), retroperitoneal white adipose tissue (rWAT), and subcutaneous white adipose tissue (scWAT). (B) Norepinephrine concentration in liver, kidney, adrenal gland, hypothalamus, and ovary tissue in rats after ICV injection with leptin (Experiment 1, see Section 4). Data are shown as mean ± SEM. * = p < 0.05; ** = p < 0.01.

Figure 2

Serum leptin levels and norepinephrine concentration in different tissues in a model of diet-induced obesity. NL means “normal litter, SL means “small litter”, SD means “standard diet” and HFD means “high-fat diet”. Rats remained with their respective diets (SD or HFD) from weaning until postnatal day 50 or 150, when they were euthanized (Experiment 1, see Section 4). (A) Serum leptin levels in rats at 50 or 150 days old. (B) Norepinephrine concentration in samples obtained from mesenteric white adipose tissue (mWAT) of rats at 50 or 150 days old. Norepinephrine concentration in the liver (C) and in the ovaries (D) of rats at 50 or 150 days old. Data are shown as mean ± SEM. * = p < 0.05; ** = p < 0.01; *** = p < 0.001.