An Acute Bout of Exercise Suppresses Appetite via Central Lactate Metabolism.

Exercise has been reported to elicit a transient suppression of appetite. Plasma lactate, which is produced by exercising muscle, is believed to have a critical effect on exercise-induced appetite suppression. However, the underlying mechanisms and signaling steps of central lactate metabolism remain unexplored. After central oxamate administration, C57BL/6J male mice performed 10 high-intensity interval running at 90% Vmax for 4 minutes each, which separated by 2 minutes at 12 m/min. Food intake and the expression of hypothalamic appetite-regulating neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were investigated following exercise training. Janus kinase 2 (Jak2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway was also determined by Western blot. In addition, hypoxia-inducible factor-1α (HIF-1α) was investigated to explore the effect of central lactate metabolism following exercise. We found that central oxamate administration reversed exercise-induced suppression of food intake, and as well as changes in the expression of POMC and NPY. Moreover, acute exercise led to an increase in the phosphorylation of Jak2 and STAT3 in the hypothalamus, while central lactate inhibition significantly blunted this effect. In addition, HIF-1α expression increased obviously after exercise, while it was attenuated by central oxamate administration. Collectively, our data reveal that central lactate metabolism mediates exercise-induced suppression of appetite and changes in neuropeptides, possibly through enhanced Jak2-STAT3 signaling.

C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation.

OBJECTIVE: C1qTNF-related protein 4 (CTRP4) acts in the hypothalamus to modulate food intake in diet-induced obese mice and has been shown to exert an anti-inflammatory effect on macrophages. Since high-fat diet-induced microglial activation and hypothalamic inflammation impair leptin signaling and increase food intake, we aimed to explore the potential connection between the anorexigenic effect of CTRP4 and the suppression of hypothalamic inflammation in mice with DIO. METHODS: Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and the hypothalamic leptin signaling pathway in diet-induced obese mice. Furthermore, central and plasma proinflammatory cytokines, including TNF-α and IL-6, were measured by Western blotting and ELISA. Changes in the hypothalamic NF-κB signaling cascade and microglial activation were also examined in vivo. In addition, NF-κB signaling and proinflammatory factors were investigated in BV-2 cells after CTRP4 intervention. RESULTS: We found that food intake was decreased, while leptin signaling was significantly improved in mice with DIO after CTRP4 overexpression. Central and peripheral TNF-α and IL-6 levels were reduced by central Ad-CTRP4 administration. Hypothalamic NF-κB signaling and microglial activation were also significantly suppressed in vivo. In addition, NF-κB signaling was inhibited in BV-2 cells following CTRP4 intervention, which was consistent with the decreased production of TNF-α and IL-6. CONCLUSIONS: Our data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.

C1q/TNF-related Protein 4 Induces Signal Transducer and Activator of Transcription 3 Pathway and Modulates Food Intake.

C1q/TNF-related protein 4 (CTRP4) has been reported to decrease food intake and regulate energy homeostasis. However, its underlying mechanism and signaling pathway remain unknown. Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and signal transducer and activator of transcription 3 (STAT3) signaling pathway in normal chow-fed mice. Expressions of neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were studied in hypothalamus by Western blot and immunochemistry. STAT3 and suppressor of cytokine signaling 3 (SOCS3) were determined by Western blot. STAT3 signaling pathway was also investigated in Neuro 2A (N2a) cells after CTRP4 overexpression intervention. We found that food intake decreased significantly in mice under normal chow condition after CTRP4 overexpression. Both immunohistochemistry and Western blot demonstrated that POMC expression was significantly increased while NPY expression was significantly decreased. The changes of neuropeptides were accompanied by significant increased STAT3 phosphorylation and decreased SOCS3 levels. The same changes of neuropeptides and STAT3 signaling were also found in N2a cells after CTRP4 overexpression intervention. Collectively, our data reveals that CTRP4 induces the activation of STAT3 signaling and decreases food intake.

Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats.

Nesfatin-1, an 82-amino acid neuropeptide, has recently been characterized as a potent metabolic regulator. However, the metabolic mechanisms and signaling steps directly associated with the action of nesfatin-1 have not been well delineated. We established a loss-of-function model of hypothalamic nesfatin-1/NUCB2 signaling in rats through an adenoviral-mediated RNA interference. With this model, we found that inhibition of central nesfatin-1/NUCB2 activity markedly increased food intake and hepatic glucose flux and decreased glucose uptake in peripheral tissue in rats fed either a normal chow diet (NCD) or a high-fat diet (HFD). The change of hepatic glucose fluxes in the hypothalamic nesfatin-1/NUCB2 knockdown rats was accompanied by increased hepatic levels of glucose-6-phosphatase and PEPCK and decreased insulin receptor, insulin receptor substrate 1, and AKT kinase phosphorylation. Furthermore, knockdown of hypothalamic nesfatin-1 led to decreased phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) and the subsequent suppressor of cytokine signaling 3 levels. These results demonstrate that hypothalamic nesfatin-1/NUCB2 plays an important role in glucose homeostasis and hepatic insulin sensitivity, which is, at least in part, associated with the activation of the mTOR-STAT3 signaling pathway.