Vagal control of satiety and hormonal regulation of appetite

Abstract

The paradigm for the control of feeding behavior has changed significantly. In this review, we present evidence that the separation of function in which cholecystokinin (CCK) controls short-term food intake and leptin regulate long-term eating behavior and body weight become less clear. In addition to the hypothalamus, the vagus nerve is critically involved in the control of feeding by transmitting signals arising from the upper gut to the nucleus of the solitary tract. Among the peripheral mediators, CCK is the key peptide involved in generating the satiety signal via the vagus. Leptin receptors have also been identified in the vagus nerve. Studies in the rodents clearly indicate that leptin and CCK interact synergistically to induce short-term inhibition of food intake and long-term reduction of body weight. The synergistic interaction between vagal CCK-A receptor and leptin is mediated by the phosphorylation of signal transducer and activator of transcription3 (STAT3), which in turn, activates closure of K(+) channels, leading to membrane depolarization and neuronal firing. This involves the interaction between CCK/SRC/phosphoinositide 3-kinase cascades and leptin/Janus kinase-2/phosphoinositide 3-kinase/STAT3 signaling pathways. It is conceivable that malfunctioning of these signaling molecules may result in eating disorders.

Keywords: Cholecystokinin; Leptin; Nodose ganglion; Signal transduction.

Figure 1

Neuroanatomically discrete populations of leptin receptor expressing neurons mediate distinct components of leptin action. The hypothalamic nuclei, including the arcuate, dorsomedial, ventromedial, lateral hypothalamic area and ventral premammillary (PMv) nuclei play an important role in the regulation of satiety and glycemic control. The hindbrain including the nucleus of the solitary tract which is activated by the vagal afferent pathway may also regulate satiety. In addition, leptin differentially regulates 2 populations of thyrotropin releasing hormone-expressing neurons in the paraventral nucleus to modulate thyroid hormone secretion via the hypothalamic-pituitary axis. Leptin also acts on neurons in the PMv and medial preoptic area to regulate reproductive function by modulating gonadotropin releasing hormone secretion. NTS, nucleus of the solitary tract; VTA, ventral tegmental area; LHA, lateral hypothalamic area; ARC, arcuate; VMH, ventromedial; PVN, paraventral nucleus; MPOA, medial preoptic area. Modified figure adopted from Robertson et al with permission from Elsevier.

Figure 2

The role of discrete leptin receptor b (LepRb) functional sites in leptin signaling. Leptin binding to LepRb activates the associated Janus kinase-2 (Jak2) tyrosine kinase bound at the Box1/2 motifs. Activated Jak2 undergoes robust autophosphorylation and phosphorylates Tyr₉₈₅, Tyr₁₀₇₇ and Tyr₁₁₃₈ on the LepRb intracellular tail. These phosphorylated residues act as docking sites for SH2-domain containing proteins. Phosphorylated Tyr₉₈₅ mediates docking with SH2 domain-containing tyrosine phosphatase 2 and subsequent activation of extracellular signal-regulated kinase through the mictogen-activated protein kinase signaling cascade. Phosphorylated Tyr₁₀₇₇ mediates signal transducer and activator of transcription 5 (STAT5) activation. Phosphorylated Tyr₁₁₃₈mediates both STAT3 and STAT5 activation. STAT3 activation ultimately leads to increased expression of suppressor of cytokine signaling-3, which acts as a feedback inhibitor and negatively regulates LepRb signaling in part by binding phosphorylated Tyr₉₈₅. Leptin also activates phosphoinositide 3-kinase, although the intermediated steps for this process remain obscure. PI3K, phosphoinositide 3-kinase; SOCS3, suppressor of cytokine signaling-3; SHP2, SH2 domain-containing tyrosine phosphatase 2; ERK, extracellular signal-regulated kinase. Modified figure adopted from Robertson et al with permission from Elsevier.

Figure 3

Interaction between cholecystokinin-8 (CCK-8) and leptin on nodose neuronal firing, and the effect of JMV-180 on this interaction. Intraarterial infusion of CCK-8 (10 pmol) (A) did not stimulate vagal nodose neuronal firing. CCK-8 at 120 pmol (B) and leptin at 225 pmol (C) increased the neuronal discharge frequency. (D) A synergistic effect was observed when CCK and leptin were infused together. (E, F) Administration of JMV-180 but not CCK-8 prevented this potentiation effect, which suggests that low-affinity CCK-A receptors are coexpressed with leptin receptors in rat nodose ganglia. Adapted from Li et al.

Figure 4

Proposed signal transduction pathways in nodose ganglia following receptor activation with leptin and cholecystokinin-8 (CCK-8). There are 2 potential pathways for phosphorylation of signal transducer and activator of transcription 3 (STAT3). Leptin activates Janus kinase-2 phosphorylation at tyrosine 1138, which directly phosphorylates STAT3, or leptin activates phophoinositide 3-kinase (PI3K) via the insulin receptor substrate, leading to STAT3 phosphorylation. CCK-8 activates PI3K via SRC and RhoA, which leads to phosphorylation of STAT3, suggesting that PI3K is central to the synergistic leptin/CCK STAT3 phosphorylation. The mitogen-activated protein kinase (MAPK) inhibitor PD98059 had no effect on leptin and CCK-8 synergism, suggesting that the leptin/CCK-8-stimulated MAPK/ extracellular signal-regulated kinase 1/2 pathway was not involved in STAT3 phosphorylation. STAT3 usually acts by stimulating the transcription of target genes, but the rapid electrophysiological effects suggest STAT3 may be involved in modifying the activity of K⁺ channels. CCKAR, CCK-A receptor; LRb, leptin receptor b; PKC, protein kinase C; JAK2, Janus kinase-2; IRS, insulin receptor substrate; SHP2, SH2 domain-containing tyrosine phosphatase 2; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; ATF-1, activating transcription factor-1; CRE, cAMP response element-binding protein; AP-1, activator protein-1. Adapted from Heldsinger et al.