STAT3 phosphorylation in central leptin resistance

Mechanism exploitation of energy homeostasis is urgently required because of the worldwide prevailing of obesity-related metabolic disorders in human being. Although it is well known that leptin plays a central role in regulating energy balance by suppressing food intake and promoting energy expenditure, the existence of leptin resistance in majority of obese individuals hampers the utilization of leptin therapy against these disorders. However, the mechanism of leptin resistance is largely unknown in spite of the globally enormous endeavors. Current theories to interpret leptin resistance include the impairment of leptin transport, attenuation of leptin signaling, chronic inflammation, ER tress, deficiency of autophagy, as well as leptin itself. Leptin-activated leptin receptor (LepRb) signals in hypothalamus via several pathways, in which JAK2-STAT3 pathway, the most extensively investigated one, is considered to mediate the major action of leptin in energy regulation. Upon leptin stimulation the phosphorylation of STAT3 is one of the key events in JAK2-STAT3 pathway, followed by the dimerization and nuclear translocation of this molecule. Phosphorylated STAT3 (p-STAT3), as a transcription factor, binds to and regulates its target gene such as POMC gene, playing the physiological function of leptin. Regarding POMC gene in hypothalamus however little is known about the detail of its interaction with STAT3. Moreover the status of p-STAT3 and its significance in hypothalamus of DIO mice needs to be well elucidated. This review comprehends literatures on leptin and leptin resistance and especially discusses what STAT3 phosphorylation would contribute to central leptin resistance.

The Phlorotannin-Rich Fraction of Ecklonia cava Extract Attenuated the Expressions of the Markers Related with Inflammation and Leptin Resistance in Adipose Tissue

Obesity is associated with systemic chronic inflammation, and it induces central leptin resistance which blocks the appetite-suppressing effect of leptin and leptin resistance in adipocytes. In the present study, we evaluated the effects of Ecklonia cava extract (ECE), which contained rich phlorotannins, on inflammation and leptin resistance in the adipose tissue of a diet-induced obese model. Effects of ECE on fat deposition, inflammation, M1/M2 macrophage, and T-cell infiltrations were investigated, and leptin resistance and SOCS3 were also measured in adipose tissue. Furthermore, ECE attenuated the expression of inflammation-related receptors such as TLR4 and RAGE and leptin resistance by reducing SOCS3 expression, increasing expression of leptin receptor in adipose tissue, and increasing lipolysis. ECE showed antiadiposity and anti-inflammatory effects, attenuated leptin resistance, and increased lipolysis in the diet-induced obese model. This study shows that ECE is a suitable dietary supplement candidate for the prevention or treatment of obesity or obesity-associated diseases, especially inflammation-related diseases.

Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets

The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.

Hypothalamic–Pituitary and Adipose Tissue Responses to the Effect of Resistin in Sheep: The Integration of Leptin and Resistin Signaling Involving a Suppressor of Cytokine Signaling 3 and the Long Form of the Leptin Receptor

We hypothesized that resistin is engaged in the development of leptin central insensitivity/resistance in sheep, which is a unique animal model to explore reversible leptin resistance. Thirty Polish Longwool ewes, which were ovariectomized with estrogen replacement, were used. Treatments consisted of the intravenous injection of control (saline) or recombinant bovine resistin (rbresistin): control (Control; n = 10), a low dose of rbresistin (R1; 1.0 μg/kg body weight (BW); n = 10), and a high dose of rbresistin (R2; 10.0 μg/kg BW; n = 10). The studies were performed during short-day (SD) and long-day (LD) photoperiods. Leptin and resistin concentrations were determined. Expression levels of a suppressor of cytokine signaling (SOCS)-3 and the long form of the leptin receptor (LeptRb) were determined in selected brain regions, including in the anterior pituitary (AP), hypothalamic arcuate nucleus (ARC), preoptic area (POA), and ventro- and dorsomedial nuclei (VMH/DMH). The results indicate that resistin induced a consistent decrease in LeptRb (except in POA) and an increase in SOCS-3 expression during the LD photoperiod in all selected brain regions. In conclusion, the results demonstrate that the action of resistin appears to be strongly associated with photoperiod-driven changes in the leptin signaling pathway, which may underlie the phenomenon of central leptin resistance.

Protection Against High-Fat Diet-Induced Obesity in Helz2-Deficient Male Mice Due to Enhanced Expression of Hepatic Leptin Receptor

Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.