Editors' ChoicePhysiology

Throttling thermogenesis with neurotensin

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Science Signaling  20 Jul 2021:
Vol. 14, Issue 692, eabl4916
DOI: 10.1126/scisignal.abl4916

Lymphatic endothelial cells release neurotensin to block thermogenesis in brown adipose tissue.

The lymphatic vasculature enables drainage of excess fluid from tissues, including adipose tissue. Li et al. identified a factor released by lymphatic endothelial cells that blocked thermogenesis in brown adipose tissue, a process that metabolizes fatty acids to produce heat. Lymphatic endothelial cells throughout the body expressed neurotensin, which encodes the peptides neurotensin (NTS) and neuromedin N. Activation of α1-adrenergic receptors in isolated brown adipose tissue increased Nts expression and the release of NTS into the medium. Lymphatic endothelial cells in adipose tissue in mice housed at a cold temperature expressed less Nts compared to those housed at a warm temperature. Cold temperatures induce the sympathetic nervous system to release norepinephrine, which activates thermogenesis in brown fat through β-adrenergic receptors. The authors found that this pathway also decreased Nts expression. Application of NTS to brown adipose tissue explants decreased the abundance of UCP-1, a protein critical for thermogenesis. Similarly, viral overexpression of NTS in mice decreased UCP-1 abundance, as well as tolerance to cold temperatures and energy expenditure. In contrast, genetic ablation of NTS in lymphatic endothelial cells increased UCP-1 abundance and cold tolerance and reduced the lipid content of brown adipose tissue. NTS increased ERK1/2 phosphorylation through the receptor NTSR2. Administration of an NTSR2 inhibitor to mice increased ERK1/2 phosphorylation, UCP-1 abundance, cold tolerance, and energy expenditure and reduced the lipid content in brown adipose tissue. In mice rendered obese through a high-fat diet, subsequent treatment with the NTSR2 inhibitor attenuated further weight gain and adiposity and increased glucose and insulin tolerance. Thus, blocking the activation of NTSR2 by NTS in lymphatic endothelial cells may be a strategy to increase thermogenesis in brown adipose tissue. The authors note that some of the effects seen in vivo may be partially mediated by neuromedin, the other gene product of Nts.

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