NT3/TrkC Pathway Modulates the Expression of UCP-1 and Adipocyte Size in Human and Rodent Adipose Tissue

Abstract

Neurotrophin-3 (NT3), through activation of its tropomyosin-related kinase receptor C (TrkC), modulates neuronal survival and neural stem cell differentiation. It is widely distributed in peripheral tissues (especially vessels and pancreas) and this ubiquitous pattern suggests a role for NT3, outside the nervous system and related to metabolic functions. The presence of the NT3/TrkC pathway in the adipose tissue (AT) has never been investigated. Present work studies in human and murine adipose tissue (AT) the presence of elements of the NT3/TrkC pathway and its role on lipolysis and adipocyte differentiation. qRT-PCR and immunoblot indicate that NT3 (encoded by NTF3) was present in human retroperitoneal AT and decreases with age. NT3 was also present in rat isolated adipocytes and retroperitoneal, interscapular, perivascular, and perirenal AT. Histological analysis evidences that NT3 was mainly present in vessels irrigating AT close associated to sympathetic fibers. Similar mRNA levels of TrkC (encoded by NTRK3) and β-adrenoceptors were found in all ATs assayed and in isolated adipocytes. NT3, through TrkC activation, exert a mild effect in lipolysis. Addition of NT3 during the differentiation process of human pre-adipocytes resulted in smaller adipocytes and increased uncoupling protein-1 (UCP-1) without changes in β-adrenoceptors. Similarly, transgenic mice with reduced expression of NT3 (Ntf3 knock-in lacZ reporter mice) or lacking endothelial NT3 expression (Ntf3flox1/flox2;Tie2-Cre+/0) displayed enlarged white and brown adipocytes and lower UCP-1 expression.ConclusionsNT3, mainly released by blood vessels, activates TrkC and regulates adipocyte differentiation and browning. Disruption of NT3/TrkC signaling conducts to hypertrophied white and brown adipocytes with reduced expression of the thermogenesis marker UCP-1.

Treatment with EV-miRNAs Alleviates Obesity-Associated Metabolic Dysfunction in Mice

“…Accordingly, EV mice showed partially decreased basal hyperinsulinemia—a desirable feature for the treatment of obesity [ 59 ]. Additionally, we observed that miR-122 inhibition had a stronger effect in the sWAT, resulting in upregulation of direct target genes with beneficial effects on obesity—including Vav1 , whose knockout displayed increased fat content by decreasing Sirt1 activity [ 60 ]; or Ntrk3 , which promotes browning [ 61 ].…”

MHO or MUO? White adipose tissue remodeling

“…White and brown adipocytes grow larger when NT-3/TRKC signaling is disrupted, and UCP1 expression is reduced. 223 Through sympathetic nerve stimulation, exposure to cold may cause upregulation of S100 calcium-binding protein B (S100B) in inguinal adipocytes. By regulating PRDM16 and causing the expression of UCP1, upregulated S100B may cause WAT browning.…”

“…Blood vessels are the main source of NT‐3 release, which activates tropomyosin receptor kinase C (TRKC) to control adipocyte differentiation and browning. White and brown adipocytes grow larger when NT‐3/TRKC signaling is disrupted, and UCP1 expression is reduced 223 …”

Neurotrophins and neural stem cells in posttraumatic brain injury repair

“…20 But as the brain matures, the level of NT-3 will decrease sharply, so its endogenous function is limited. 21 Similarly, NT-4/5 plays a key role in cell survival and synaptic plasticity. 22 Relevant studies have proved that various neurotrophins can combine with tropomyosin-related kinase (Trk) receptor and p75 neurotrophic factor receptor (p75NTR) to exert their neurotrophic effects and regulate nerve inflammation and myelin sheath growth; meanwhile, it could modulate cell apoptosis, stimulate neuron survival, promote the maintenance of the CNS as well as neural functional recovery, and participate in repair after TBI injury.…”

“…In the development of CNS, NT‐3 is involved in the growth of neural connections and the formation of synapses, and NT‐3 is superior to NGF or BDNF in promoting axon regeneration 20 . But as the brain matures, the level of NT‐3 will decrease sharply, so its endogenous function is limited 21 . Similarly, NT‐4/5 plays a key role in cell survival and synaptic plasticity 22 …”