Adipose tissue is one of the largest organs and a major regulator of metabolic homeostasis in mammals. Though its primary function is lipid storage, it affects metabolism via various routes. Several studies have demonstrated that adipose tissue is an important endocrine organ. Adipose tissue-derived secretary proteins, from either the adipocytes or stromal vascular fraction (SVF), tightly modulate the metabolic activity in many organs. One such well-known factor is leptin, which is an adipose tissue-derived secretory protein that regulates multiple aspects of metabolism via interactions with the leptin receptor. Adipose tissue also can affect the physiological function of skeletal muscle via the secretory protein myostatin. In addition to endocrine activity, adipose tissue-derived secretory proteins can regulate metabolic homeostasis via autocrine or paracrine signaling as well.
Neurotensin (NTS) is a 13-amino acid secretory peptide with diverse functions that acts upon both the central nervous system (CNS) and peripheral tissues. Due to its very short half-life in the circulation, the native NTS can only exert its functions via the paracrine or autocrine mode. NTS was previously known to be produced by neurons and intestinal N cells. Two G protein-coupled receptors (GPCRs), NTSR1 and NTSR2, have been discovered to specifically interact with NTS. The type I membrane glycoprotein Sortilin (SORT1 or NTSR3) also interacts with NTS, though its downstream signaling is largely uncharacterized. Many of these studies attributed the decreases in food intake to the local and direct interaction between NTS and cells in the CNS, as intracerebroventricular (ICV) injection of NTS was sufficient to reduce food intake. The feeding behavior changes induced by NTS treatment is likely mediated by NTSR1, though the role of NTSR2 cannot be excluded.
As far as we know, it is unknown whether NTS can regulate food intake through direct interactions with peripheral tissues or organs in physiological conditions. One possible reason is that for a long period, people believe that NTS is only produced by either the CNS or intestinal N cells. Though the results of ICV injection indicated that NTS could regulate food intake via direct interactions with the CNS, it did not rule out the possibility that NTS could also regulate food intake via interacting with peripheral tissues in physiological conditions.
With single-cell RNA-sequencing (scRNA-seq) analysis, we have determined that NTS was also produced specifically by lymphatic endothelial cells (LECs) as an anti-thermogenic peptide in brown adipose tissues(BATs) and a pro-lipid absorption peptide regulating the development of atherosclerosis in intestines. Ntsr2, but not Ntsr1, is widely expressed in brown adipocytes, beige adipocytes and white adipocytes. Transient knockdown experiments have indicated that NTS exerts its anti-thermogenic effects via the interactions with NTSR2 in brown adipose tissues through paracrine signaling. However, the cell-type-specific effects and long-term physiological functions of NTSR2, especially how it functions in the white adipocytes, are still unknown.
Ceramide is a kind of lipid with diverse biological functions. The metabolism of ceramide is extremely complicated, as these lipids can be synthesized and degraded by a large collection of enzymes in various pathways. It has been reported that depletion of ceramide synthetase 2 (CerS2) led to the downregulation of ceramides C20–C24 and upregulation of C16 due to compensatory effects in the liver. In addition, it has been demonstrated that ceramides C20–C24 are negative regulators of the unfolded protein response (UPR). The UPR, as a part of the integrative stress response, may affect the production of growth differentiation factor 15 (GDF15), a secretory protein. On one hand, GDF15 treatment suppresses food intake and decreases body weight via interacting with its receptor, GFRAL, in the area postrema/nucleus of the solitary tract region of the CNS; on the other hand, depletion of Gdf15 or Gfral gene leads to increases in food intake and body weight.
