Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes in rats.

The lateral hypothalamic area (LHA) integrates homeostatic processes and reward-motivated behaviors. Here we show that LHA neurons that produce melanin-concentrating hormone (MCH) are dynamically responsive to both food-directed appetitive and consummatory processes in male rats. Specifically, results reveal that MCH neuron Ca2+ activity increases in response to both discrete and contextual food-predictive cues and is correlated with food-motivated responses. MCH neuron activity also increases during eating, and this response is highly predictive of caloric consumption and declines throughout a meal, thus supporting a role for MCH neurons in the positive feedback consummatory process known as appetition. These physiological MCH neural responses are functionally relevant as chemogenetic MCH neuron activation promotes appetitive behavioral responses to food-predictive cues and increases meal size. Finally, MCH neuron activation enhances preference for a noncaloric flavor paired with intragastric glucose. Collectively, these data identify a hypothalamic neural population that orchestrates both food-motivated appetitive and intake-promoting consummatory processes.

The physiological control of eating: signals, neurons, and networks.

During the past 30 yr, investigating the physiology of eating behaviors has generated a truly vast literature. This is fueled in part by a dramatic increase in obesity and its comorbidities that has coincided with an ever increasing sophistication of genetically based manipulations. These techniques have produced results with a remarkable degree of cell specificity, particularly at the cell signaling level, and have played a lead role in advancing the field. However, putting these findings into a brain-wide context that connects physiological signals and neurons to behavior and somatic physiology requires a thorough consideration of neuronal connections: a field that has also seen an extraordinary technological revolution. Our goal is to present a comprehensive and balanced assessment of how physiological signals associated with energy homeostasis interact at many brain levels to control eating behaviors. A major theme is that these signals engage sets of interacting neural networks throughout the brain that are defined by specific neural connections. We begin by discussing some fundamental concepts, including ones that still engender vigorous debate, that provide the necessary frameworks for understanding how the brain controls meal initiation and termination. These include key word definitions, ATP availability as the pivotal regulated variable in energy homeostasis, neuropeptide signaling, homeostatic and hedonic eating, and meal structure. Within this context, we discuss network models of how key regions in the endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, and spinal cord work together with the gastrointestinal tract to enable the complex motor events that permit animals to eat in diverse situations.

Melanin-concentrating hormone and food intake control: Sites of action, peptide interactions, and appetition.

Given the increased prevalence of obesity and its associated comorbidities, understanding the mechanisms through which the brain regulates energy balance is of critical importance. The neuropeptide melanin-concentrating hormone (MCH) is produced in the lateral hypothalamic area and the adjacent incerto-hypothalamic area and promotes both food intake and energy conservation, overall contributing to body weight gain. Decades of research into this system has provided insight into the neural pathways and mechanisms (behavioral and neurobiological) through which MCH stimulates food intake. Recent technological advancements that allow for selective manipulation of MCH neuron activity have elucidated novel mechanisms of action for the hyperphagic effects of MCH, implicating neural "volume" transmission in the cerebrospinal fluid and sex-specific effects of MCH on food intake control as understudied areas for future investigation. Highlighted here are historical and recent findings that illuminate the neurobiological mechanisms through which MCH promotes food intake, including the identification of various specific neural signaling pathways and interactions with other peptide systems. We conclude with a framework that the hyperphagic effects of MCH signaling are predominantly mediated through enhancement of an "appetition" process in which early postoral prandial signals promote further caloric consumption.

Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. METHODS: We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization. RESULTS: GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. CONCLUSIONS: Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity.

Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways.

Feeding behavior rarely occurs in direct response to metabolic deficit, yet the overwhelming majority of research on the biology of food intake control has focused on basic metabolic and homeostatic neurobiological substrates. Most animals, including humans, have habitual feeding patterns in which meals are consumed based on learned and/or environmental factors. Here we illuminate a novel neural system regulating higher-order aspects of feeding through which the gut-derived hormone ghrelin communicates with ventral hippocampus (vHP) neurons to stimulate meal-entrained conditioned appetite. Additional results show that the lateral hypothalamus (LHA) is a critical downstream substrate for vHP ghrelin-mediated hyperphagia and that vHP ghrelin activated neurons communicate directly with neurons in the LHA that express the neuropeptide, orexin. Furthermore, activation of downstream orexin-1 receptors is required for vHP ghrelin-mediated hyperphagia. These findings reveal novel neurobiological circuitry regulating appetite through which ghrelin signaling in hippocampal neurons engages LHA orexin signaling.

Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling.

Neuronal protein-tyrosine phosphatase 1B (PTP1B) deficiency in mice results in enhanced leptin signaling and protection from diet-induced obesity; however, whether additional signaling pathways in the brain contribute to the metabolic effects of PTP1B deficiency remains unclear. Here, we show that the tropomyosin receptor kinase B (TrkB) receptor is a direct PTP1B substrate and implicate PTP1B in the regulation of the central brain-derived neurotrophic factor (BDNF) signaling. PTP1B interacts with activated TrkB receptor in mouse brain and human SH-SY5Y neuroblastoma cells. PTP1B overexpression reduces TrkB phosphorylation and activation of downstream signaling pathways, whereas PTP1B inhibition augments TrkB signaling. Notably, brains of Ptpn1(-/-) mice exhibit enhanced TrkB phosphorylation, and Ptpn1(-/-) mice are hypersensitive to central BDNF-induced increase in core temperature. Taken together, our findings demonstrate that PTP1B is a novel physiological regulator of TrkB and that enhanced BDNF/TrkB signaling may contribute to the beneficial metabolic effects of PTP1B deficiency.

Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling.

BACKGROUND: The stomach-derived hormone ghrelin drives higher-order feeding processes related to food reward and food seeking via central nervous system signaling at its receptor (GHSR1A). The specific nuclei mediating these effects are only partially understood. Here, we use a rat model to examine whether ghrelin signaling in the ventral subregion of the hippocampus (VHPC), a brain substrate of recent interest in energy balance control, affects learned and motivational aspects of feeding behavior. METHODS: The effects of VHPC ghrelin administration were examined on feeding-relevant behavioral paradigms, including meal pattern analysis, operant lever pressing for sucrose, and conditioned stimulus-induced feeding. The intracellular signaling and downstream neuronal pathways stimulated by VHPC GHSR1A activation were assessed with immunoblot analysis and behavioral pharmacology. RESULTS: Ghrelin delivery to the VHPC but not the dorsal hippocampus increased food intake primarily by increasing meal frequency. Intra-VHPC ghrelin delivery also increased willingness to work for sucrose and increased spontaneous meal initiation in nondeprived rats after the presentation of a conditioned stimulus that previously signaled meal access when the rats were food-restricted. The food intake enhancing effects of VHPC ghrelin were blocked by co-administration of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). Immunoblot analyses provided complementary support for ghrelin activated PI3K-Akt signaling in the VHPC and revealed that this activation is blunted with high-fat diet consumption. Other immunoblot results show that VHPC GHSR1A signaling activates downstream dopaminergic activity in the nucleus accumbens. CONCLUSIONS: These findings illuminate novel neuronal and behavioral mechanisms mediating ghrelinergic control of cognitive aspects of feeding control.

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. POMC neuron-specific deletion of PTP1B in mice results in reduced high-fat diet-induced body weight and adiposity gain due to increased energy expenditure and greater leptin sensitivity. Mice lacking the leptin gene (ob/ob mice) are hypothermic and cold intolerant, whereas leptin delivery to ob/ob mice induces thermogenesis via increased sympathetic activity to brown adipose tissue (BAT). Here, we examined whether POMC PTP1B mediates the thermoregulatory response of CNS leptin signaling by evaluating food intake, body weight, core temperature (T(C)), and spontaneous physical activity (SPA) in response to either exogenous leptin or 4-day cold exposure (4°C) in male POMC-Ptp1b-deficient mice compared with wild-type controls. POMC-Ptp1b(-/-) mice were hypersensitive to leptin-induced food intake and body weight suppression compared with wild types, yet they displayed similar leptin-induced increases in T(C). Interestingly, POMC-Ptp1b(-/-) mice had increased BAT weight and elevated plasma triiodothyronine (T(3)) levels in response to a 4-day cold challenge, as well as reduced SPA 24 h after cold exposure, relative to controls. These data show that PTP1B in POMC neurons plays a role in short-term cold-induced reduction of SPA and may influence cold-induced thermogenesis via enhanced activation of the thyroid axis.