Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling.

Background: The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylin's effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals.

Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control.

Alhough the glucagon-like peptide-1 (GLP-1) system is critical to energy balance control and is a target for obesity pharmacotherapies, the receptor-population-mediating effects of endogenous GLP-1 signaling are not fully understood. To address this, we developed a novel adeno-associated virus (AAV-GLP-1R) that utilizes short hairpin RNA to chronically knock down GLP-1 receptors (GLP-1R) in rats. As pharmacological studies highlight the hindbrain nucleus tractus solitarius (NTS) as a brain region important for GLP-1R-mediated effects on energy balance, AAV-GLP-1R was injected into the NTS to examine the role of endogenous NTS GLP-1R signaling in energy balance control.

Binge-type eating disrupts dopaminergic and GABAergic signaling in the prefrontal cortex and ventral tegmental area.

Objective: Binge eating is characterized by repeated intermittent bouts of compulsive overconsumption of food. Treatment is challenging given limited understanding of the mechanisms underlying this type of disordered eating. The hypothesis that dysregulation of mesocortical dopaminergic and GABAergic systems underlie binge eating was tested.

Astrocytes Regulate GLP-1 Receptor-Mediated Effects on Energy Balance.

Unlabelled: Astrocytes are well established modulators of extracellular glutamate, but their direct influence on energy balance-relevant behaviors is largely understudied. As the anorectic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists are partly mediated by central modulation of glutamatergic signaling, we tested the hypothesis that astrocytic GLP-1R signaling regulates energy balance in rats. Central or peripheral administration of a fluorophore-labeled GLP-1R agonist, exendin-4, localizes within astrocytes and neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus critical for energy balance control.

Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine.

Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved treatments. Thus, there is a clear need to identify and develop novel pharmacotherapies for cocaine addiction. Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors in the ventral tegmental area (VTA) reduces intake of highly palatable food.

Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance.

Objective: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), play a paramount role in the central regulation of energy balance. Despite the substantial body of genetic evidence implicating BDNF- or TrkB-deficiency in human obesity, the critical brain region(s) contributing to the endogenous role of BDNF/TrkB signaling in metabolic control remain unknown.

Methods: We assessed the importance of intact hypothalamic or hindbrain TrkB signaling in central regulation of energy balance by generating Nkx2.

Amylin modulates the mesolimbic dopamine system to control energy balance.

Amylin acts in the CNS to reduce feeding and body weight. Recently, the ventral tegmental area (VTA), a mesolimbic nucleus important for food intake and reward, was identified as a site-of-action mediating the anorectic effects of amylin. However, the long-term physiological relevance and mechanisms mediating the intake-suppressive effects of VTA amylin receptor (AmyR) activation are unknown.

Improved metabolic phenotype of hypothalamic PTP1B-deficiency is dependent upon the leptin receptor.

Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of central metabolic signaling, and mice with whole brain-, leptin receptor (LepRb) expressing cell-, or proopiomelanocortin neuron-specific PTP1B-deficiency are lean, leptin hypersensitive, and display improved glucose homeostasis. However, whether the metabolic effects of central PTP1B-deficiency are due to action within the hypothalamus remains unclear. Moreover, whether or not these effects are exclusively due to enhanced leptin signaling is unknown.

Hindbrain GLP-1 receptor-mediated suppression of food intake requires a PI3K-dependent decrease in phosphorylation of membrane-bound Akt.

Glucagon-like peptide-1 (GLP-1) receptors (GLP-1R) expressed in the nucleus tractus solitarius (NTS) are physiologically required for the control of feeding. Recently, NTS GLP-1R-mediated suppression of feeding was shown to occur via a rapid PKA-induced suppression of AMPK and activation of MAPK signaling. Unknown are the additional intracellular signaling pathways that account for the long-term hypophagic effects of GLP-1R activation.

Amylin receptor signaling in the ventral tegmental area is physiologically relevant for the control of food intake.

The ability of amylin, a pancreatic β-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward.

Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning.

ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates ß-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP-PTP1B, are present in dendritic spines of hippocampal neurons in culture.

Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice.

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed tyrosine phosphatase implicated in the negative regulation of leptin and insulin receptor signaling. PTP1B(-/-) mice possess a lean metabolic phenotype attributed at least partially to improved hypothalamic leptin sensitivity. Interestingly, mice lacking both leptin and PTP1B (ob/ob:PTP1B(-/-)) have reduced body weight compared with mice lacking leptin only, suggesting that PTP1B may have important leptin-independent metabolic effects.

Food intake reductions and increases in energetic responses by hindbrain leptin and melanotan II are enhanced in mice with POMC-specific PTP1B deficiency.

Leptin regulates energy balance through central circuits that control food intake and energy expenditure, including proopiomelanocortin (POMC) neurons. POMC neuron-specific deletion of protein tyrosine phosphatase 1B (PTP1B) (Ptpn1(loxP/loxP) POMC-Cre), a negative regulator of CNS leptin signaling, results in resistance to diet-induced obesity and improved peripheral leptin sensitivity in mice, thus establishing PTP1B as an important component of POMC neuron regulation of energy balance. POMC neurons are expressed in the pituitary, the arcuate nucleus of the hypothalamus (ARH), and the nucleus of the solitary tract (NTS) in the hindbrain, and it is unknown how each population might contribute to the phenotype of POMC-Ptp1b(-/-) mice.

Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress.

Obesity is associated with induction of the ER (endoplasmic reticulum)-stress response signalling and insulin resistance. PTP1B (protein tyrosine phosphatase 1B) is a major regulator of adiposity and insulin sensitivity. The aim of the present study was to investigate the role of L-PTP1B (liver-specific PTP1B) in chronically HFD (high-fat diet) and pharmacologically induced (tunicamycin and thapsigargin) ER-stress response signalling in vitro and in vivo.

Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure.

The adipose tissue-derived hormone leptin regulates energy balance through catabolic effects on central circuits, including proopiomelanocortin (POMC) neurons. Leptin activation of POMC neurons increases thermogenesis and locomotor activity. Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin signaling.

Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation.

Glucagon-like peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (fourth i.c.

PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice.

Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron-specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b-/- mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2-/- mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure.

Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress.

Objective: The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B(-/-) mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B(-/-) mice are protected against high-fat diet-induced obesity and glucose intolerance, whereas muscle-specific PTP1B(-/-) mice have increased insulin sensitivity independent of changes in adiposity.