Abstract
ObjectiveC1qTNF-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.MethodsUsing 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.ResultsWe 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.ConclusionsOur data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.
Highlights
In anorexigenic proopiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/Cocaine- and amphetamine-regulated transcript (CART)) neurons and orexigenic agouti-related peptide/neuropeptide Y (AgRP/Neuropeptide Y (NPY)) neurons, the hypothalamic leptinYe et al Journal of Neuroinflammation (2021) 18:159 morphology [5]
We explored the effects of C1qTNF-related protein 4 (CTRP4) on energy homeostasis and revealed that central Ad-CTRP4 intervention caused significant decreases in food intake in high-fat diet (HFD)-fed mice between days 2 and 7 (Fig. 1c)
We examined the effects of central CTRP4 on peripheral metabolism and found that the levels of fasting plasma glucose, TG, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and glycosylated serum protein (GSP) were not affected by CTRP4 intervention (Table 1)
Summary
In anorexigenic proopiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons and orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons, the hypothalamic leptinYe et al Journal of Neuroinflammation (2021) 18:159 morphology [5]. The CTRP ( referred to as C1qTNF-related protein) family, which features a highly conserved Cterminal complement C1q domain [11], belongs to the adipokine family [12]. It plays important roles in multiple physiological processes, such as inflammation and metabolism [13, 14]. Given that CTRP4 is able to suppress lipopolysaccharide (LPS)-induced proinflammatory cytokine production in macrophages by reducing NF-κB and signal transducer and activator of transcription 3 (STAT3) activation [17], there may be a connection between the anorexigenic effect of CTRP4 and hypothalamic inflammation in mice with DIO
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