Visfatin Triggers Anorexia and Body Weight Loss through Regulating the Inflammatory Response in the Hypothalamic Microglia

Abstract

Visfatin is an adipokine that is secreted from adipose tissue, and it is involved in a variety of physiological processes. In particular, visfatin has been implicated in metabolic diseases, such as obesity and type 2 diabetes, which are directly linked to systemic inflammation. However, the potential impacts of visfatin on the hypothalamic control of energy homeostasis, which is involved in microglial inflammation, have not fully been investigated. In this study, we found that treatment with exogenous recombinant visfatin protein led to the activation of the inflammatory response in a microglial cell line. In addition, we observed that central administration of visfatin led to the activation of microglia in the hypothalamus. Finally, we found that visfatin reduced food intake and body weight through activating POMC neurons in association with microglia activation in mice. These findings indicate that elevation of central visfatin levels may be associated with homeostatic feeding behavior in response to metabolic shifts, such as increased adiposity following inflammatory processes in the hypothalamus.

Adiponectin Controls Nutrient Availability in Hypothalamic Astrocytes

“…In particular, adipose tissue dynamically communicates with the hypothalamus through its own chemical messengers termed adipokines [17,18]. Notably, the circulating levels of most adipokines are proportional to adiposity and long-term elevation of adipokines elicits adverse effects, such as inflammation, oxidative stress, and endoplasmic reticulum stress, which might comprise potential pathogenic elements for the development of metabolic disorders [19].…”

Obesity induced by estrogen deficiency is associated with hypothalamic inflammation

“…Previous studies and our study both observe that OVX mice, an experimental mouse model for menopause, displayed visceral obesity showing increased body weight and adiposity [ 29 ]. Moreover, numerous studies have reported that sustained elevation of substances derived from visceral fats triggers hypothalamic inflammation concomitant with reactive gliosis [ 30 , 31 ]. In agreement with this, we successfully confirmed that OVX mice showed elevated hypothalamic inflammation by analyzing the expression of genes involved in cellular inflammatory responses.…”

Microglial regulation of satiety and cognition

“…Microglia do have an established role in the anorexia associated with sickness behaviour: the collective fever, withdrawal, and appetite suppression that is seen in response to neuroimmune challenge . Microglia are likely to be involved in all aspects of this response, and microglial activation with visfatin or TLR2 activation leads to increases in pro‐opiomelanocortin (POMC) neuronal activity and a suppression of food intake co‐incident with other aspects of the sickness response …”

“…96 Microglia are likely to be involved in all aspects of this response, and microglial activation with visfatin or TLR2 activation leads to increases in pro-opiomelanocortin (POMC) neuronal activity and a suppression of food intake co-incident with other aspects of the sickness response. 97,98 Microglia may also be involved in the dysregulated appetite associated with obesity. Microglial activation is a key factor in obesity and can be seen in the brain prior to evidence of peripheral inflammation.…”

“…Learning-induced microglial activation may also orchestrate strategic remodelling of dendritic spines, which is essential for successful cognition. Figure (95) LPS in arcute nucleus slice preparations: mouse & rat (108) ICV TLR2 activation: mouse (97) ICV minocycline: rat (108) Cx3cr1-Dtr rats (acute conditional microglial knockout: rat (20) PLX5622 in HFD: mouse (106) Drinking water depletion minocycline: mouse (65) CSFR1 inhibition with PLX compounds: mouse (21,106,107) Ara-C (in cases of normal chow): mouse (102) Ara-C (in cases of HFD): mouse (102) Annexin-V (in cases of HFD): mouse (65) Annexin-V (in cases of normal chow): mouse (65) Minocycline: humans (112) Microglial leptin receptor depletion: mouse (110) Embroyonic microglial depletion: mouse (111) ICV visfatin: mouse (96) Obesity (males but not females): mouse & rat (98,101,104) HFD: mouse & rat (99,100,101) the basolateral amygdala, a circuit that interacts with the orexigenic networks of the PVT to establish valence in satiety-sensing. 115,116 In support of this idea, we see greater neuronal activation in the PVT in response to feeding in the absence of microglia.…”