Circulating NGAL accelerates diet-induced obesity through local inhibition of thermogenic beta3 adrenergic nerve/brown adipose tissue axis

• Published in: Proceedings for Annual Meeting of The Japanese Pharmacological Society Vol. WCP2018; p. OR29-3
• Main Authors: Ishii, Akira, Katsuura, Goro, Imamaki, Hirotaka, Kimura, Hiroyuki, Mori, Keita P., Yokoi, Hideki, Ohinata, Kousaku, Tsuchida, Junichi, Nakao, Kazuwa, Yanagita, Motoko, Mukoyama, Masashi, Mori, Kiyoshi
• Format: Journal Article
• Language: English
• Published: Japanese Pharmacological Society 2018
• Subjects: energy homeostasis; NGAL; sympathetic nerve activity
• ISSN: 2435-4953; 2435-4953
• DOI: 10.1254/jpssuppl.WCP2018.0_OR29-3

[Background] Neutrophil gelatinase-associated lipocalin (NGAL or LCN2) is an iron carrier protein having numerous biological activities including activation of kidney differentiation and modulation of kidney injury. Serum NGAL level is increased by kidney injury, bacterial infection, cancer and obesity. We have reported that serum NGAL levels in hemodialysis patients are positively correlated to nutritional status. [Methods]To study a pathophysiological role of NGAL in obesity and energy homeostasis, we examined responses of wild-type (WT), NGAL knockout (KO) and liver-specific NGAL transgenic (Tg) mice to high fat diet (HFD) or cold exposure.[Results]Under HFD treatment, NGAL KO mice exhibited larger brown adipose tissues (BAT), upregulation of thermogenic gene expression in BAT, consumed more oxygen, ate more food and gained less body weights compared to WT mice, suggesting increased energy expenditure in NGAL KO mice. Obesity resistance in NGAL KO mice was completely rescued in NGAL KO+Tg mice, in which NGAL gene was systemically disrupted but overexpressed in liver. HFD caused systemic activation of sympathetic nerves leading to hypertension and increased urinary noradrenaline excretion in WT mice, but these were not observed in KO mice reflecting lean phenotypes. Under cold exposure, NGAL KO mice showed higher body temperature, more intense 18F-fluorodeoxyglucose uptake in BAT and upregulation of thermogenic gene expression in BAT compared to WT mice. On the other hand, NGAL Tg mice showed lower body temperature compared to WT mice. Furthermore, BAT noradrenaline levels were significantly lower in KO mice and significantly higher in Tg mice compared to WT mice. Recent other studies elucidated that activation of beta3 adrenergic nerve/BAT axis results in paradoxical decrease of BAT noradrenaline contents by enhanced noradrenaline turnover. These findings suggest that sympathetic nerve activity at BAT endings might be enhanced in KO mice and suppressed in Tg mice compared to WT mice after cold exposure. Administration of beta3 adrenergic receptor blocker or iron-loaded (but not iron-free) NGAL canceled the difference between body temperature of KO and WT mice during cold exposure. [Conclusions]Circulating NGAL possesses obesity-promoting and anti-thermogenic effects likely through inhibition of sympathetic nerve activity at BAT endings in an iron-dependent manner.