Adipocyte‐derived extracellular vesicles modulate appetite and weight through mTOR signalling in the hypothalamus

Abstract

Aim Type 2 diabetes and obesity are diseases related to surplus energy in the body. Abnormal interaction between the hypothalamus and adipose tissues is a key trigger of energy metabolism dysfunction. Extracellular vesicles (EVs) regulate intercellular communication by transporting intracellular cargo to recipient cells thereby altering the function of recipient cells. This study aimed to evaluate whether adipocyte‐derived EVs can act on hypothalamic neurons to modulate energy intake and to identify the EV‐associated non‐coding RNAs. Methods Confocal imaging was used to trace the uptake of labelled adipocyte‐derived exosomes by hypothalamic anorexigenic POMC neurons. The effects of adipocyte‐derived EVs on the mammalian target of rapamycin (mTOR) signalling pathway in POMC neurons were evaluated based on mRNA and protein expression in vitro using quantitative real‐time PCR and western blotting. In addition, adipocyte‐derived EVs were injected into recipient mice, and changes in mice body weight and daily food intake were monitored. The biological effects of the EV‐associated MALAT1 on POMC neurons were explored. Results Adipocyte‐derived EVs were successfully transferred into POMC neurons in vitro. Results showed that adipocytes of obese mice secreted MALAT1‐containing EVs, which increased appetite and weight when administered to lean mice. Conversely, adipocyte‐derived EVs from lean mice decreased food intake and weight when administered to obese mice. Conclusion Adipocyte‐derived EVs play important roles in mediating the interaction between adipocytes and hypothalamic neurons. Adipocyte‐derived EVs can regulate POMC expression through the hypothalamic mTOR signalling in vivo and in vitro, thereby affecting body energy intake.

Adipocyte‐derived extracellular vesicles as new communication signals in the regulation of food intake

“…These adipose‐derived EVs were then fluorescent labelled and incubated with the embryonic rat hypothalamus R13 cells. There was a significant uptake of the label in these cells after 3 hours (Figure 1D from). The cell line has been derived from rat embryonic hypothalamic primary culture cells (day 18), which were immortalized by retroviral transfer of SV40 T‐Ag; these cells show the following markers—strong for agouti‐related peptide (AgRP), oestrogen receptor (ER)beta, insulin receptor (IR), neuropeptide Y (NPY), leptin receptor b (OBRb), oxytocin and plus for proopiomelanocortin (POMC) and melanin‐concentrating hormone (MCH) (Figure 2 from).…”

“…Gao and colleagues evaluated whether adipocyte‐derived EVs can act on hypothalamic neurons to modulate energy intake. In order to approach their hypothesis, the authors designed a series of in vitro and in vivo experiments: Testing the uptake of EVs by a rat hypothalamus cell line in vitro. …”

“…Using mouse 3T3 cells, isolated adipocytes from male C57BL/6J mice and Wistar rats, the authors could demonstrate the secretion of exosomes in the culture medium by measurement of the EV‐associated protein markers CD9, CD63 and TSG101 (Figure 1B from). The EVS had a diameter of 30‐200 nm (Figure 1C from). Interestingly, they did not find any difference in the abundance of the EVs‐associated protein markers between lean and obese adipocytes.…”

Adipose tissue—more than just fat

“…Dysregulation of signalling pathways of hypothalamic and peripheral tissues leads to a dysfunctional regulation of energy intake. In this context, Gao et al did show that adipocyte‐derived extracellular vesicles can enter hypothalamic anorexigenic neurons in the brain. They contain MALAT1 (metastasis‐associated lung adenocarcinoma transcript‐1), which acts as a competitive endogenous RNA and activates the mTOR (mammalian target of rapamycin) signalling downregulating POMC protein expression.…”

“…A number of articles addressing basic mechanisms related to obesity have recently appeared in Acta physiologica. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] One area of clinical relevance for obese patients is the immune system. Duan et al 20 recapitulate the connections between a high-fat diet and diseases.…”