The lateral parabrachial nucleus is a site of action for neuroendocrine signaling effects on food intake

The dramatic increase in obesity and its associated comorbidities is a major public health concern. Given that obesity can be caused by increased calorie intake, it is necessary to understand the neural control of food intake in order to develop more effective obesity treatments. However, our knowledge of the brain regions and signaling mechanisms that are involved in energy balance is incomplete. This dissertation focuses on a relatively understudied brain region, the lateral parabrachial nucleus (lPBN), and its contributions to food intake control. The presence of receptors in lPBN neurons for various key neuroendocrine signals, including glucagon-like peptide-1 (GLP-1), leptin, and peptide YY (PYY), led me to hypothesize that these peptides act within the lPBN to affect food intake. To test this hypothesis, I gave microinjections of these peptides, and/or receptor agonists and antagonists, directly into the lPBN and measured a variety of food intake-relevant measures in rats. First, I showed that lPBN GLP-1R stimulation reduces chow and high-fat diet intake, likely through direct projections from GLP-1-producing neurons in the nucleus tractus solitarius (NTS). Conversely, lPBN GLP-1R blockade increased chow and high-fat diet intake, demonstrating that endogenous lPBN GLP-1R signaling is physiologically relevant to the control of food intake. lPBN GLP-1R stimulation also decreased progressive ratio (PR) operant responding for palatable food, suggesting a role for lPBN GLP-1R signaling in food reward. Next, I showed that lPBN leptin injection significantly reduced chow and high-fat diet intake by reducing meal size, indicating possible interactions between lPBN leptin signaling and the processing of gastrointestinal satiation signaling. Leptin receptor signaling in the lPBN, however, had no effect on gastric emptying or on food reward parameters [i.e. PR responding and conditioned place preference for palatable food]. Finally, I demonstrated that both biologically active isoforms of PYY [(1-36) and (3-36)] increase food intake by potently increasing meal size, effects which may be mediated by neuronal projections from gigantocellular reticular nucleus PYY-producing neurons to the lPBN. Quantitative polymerase chain reaction data revealed that of the Y family of receptors that bind PYY, the Y1 receptor was most highly expressed in the lPBN. Behavioral results confirmed that pretreatment with a selective Y1 receptor antagonist abolished the intake-stimulatory effects of lPBN PYY (3-36), suggesting that the Y1 receptor mediates the hyperphagic effects of lPBN PYY. Taken together, these data are the first to show that multiple neuroendocrine peptides known to regulate food intake and energy balance, i.e. GLP-1, leptin, and PYY, can act in the lPBN to affect food intake. Overall, my results highlight the lPBN as a key nucleus in the distributed central nervous system control of food intake and energy balance

Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity

Summary: The brain regulates food intake by processing sensory cues and peripheral physiological signals, but the neural basis of this integration remains unclear. Hypothalamic, agouti-related protein (AgRP)-expressing neurons are critical regulators of food intake. AgRP neuron activity is high during hunger and is rapidly reduced by the sight and smell of food. Here, we reveal two distinct components of AgRP neuron activity regulation: a rapid but transient sensory-driven signal and a slower, sustained calorie-dependent signal. We discovered that nutrients are necessary and sufficient for sustained reductions in AgRP neuron activity and that activity reductions are proportional to the calories obtained. This change in activity is recapitulated by exogenous administration of gut-derived satiation signals. Furthermore, we showed that the nutritive value of food trains sensory systems—in a single trial—to drive rapid, anticipatory AgRP neuron activity inhibition. Together, these data demonstrate that nutrients are the primary regulators of AgRP neuron activity. : Su et al. demonstrate that nutrient content in the GI tract is rapidly signaled to hypothalamic neurons activated by hunger. This rapid effect is mediated by three satiation signals that synergistically reduce the activity of AgRP neurons. These findings uncover how hunger circuits in the brain are regulated and raise the possibility that hunger can be pharmacologically controlled. Keywords: calcium imaging, AgRP neurons, calories, satiation signals, sensory regulation, single trial learning, cholecystokinin, CCK, peptide tyrosine tyrosine, PYY, amylin, homeostasi

Anti-inflammatory effects of hunger are transmitted to the periphery via projection-specific AgRP circuits

Summary: Caloric restriction has anti-inflammatory effects. However, the coordinated physiological actions that lead to reduced inflammation in a state of caloric deficit (hunger) are largely unknown. Using a mouse model of injury-induced peripheral inflammation, we find that food deprivation reduces edema, temperature, and cytokine responses that occur after injury. The magnitude of the anti-inflammatory effect that occurs during hunger is more robust than that of non-steroidal anti-inflammatory drugs. The effects of hunger are recapitulated centrally by activity in nutrient-sensing hypothalamic agouti-related protein (AgRP)-expressing neurons. We find that AgRP neurons projecting to the paraventricular nucleus of the hypothalamus rapidly and robustly reduce inflammation and mediate the majority of hunger’s anti-inflammatory effects. Intact vagal efferent signaling is required for the anti-inflammatory action of hunger, revealing a brain-to-periphery pathway for this reduction in inflammation. Taken together, these data begin to unravel a potent anti-inflammatory pathway engaged by hypothalamic AgRP neurons to reduce inflammation

AgRP neuron activity promotes associations between sensory and nutritive signals to guide flavor preference

Objective: The learned associations between sensory cues (e.g., taste, smell) and nutritive value (e.g., calories, post-ingestive signaling) of foods powerfully influences our eating behavior [1], but the neural circuits that mediate these associations are not well understood. Here, we examined the role of agouti-related protein (AgRP)-expressing neurons – neurons which are critical drivers of feeding behavior [2; 3] – in mediating flavor-nutrient learning (FNL). Methods: Because mice prefer flavors associated with AgRP neuron activity suppression [4], we examined how optogenetic stimulation of AgRP neurons during intake influences FNL, and used fiber photometry to determine how endogenous AgRP neuron activity tracks associations between flavors and nutrients. Results: We unexpectedly found that tonic activity in AgRP neurons during FNL potentiated, rather than prevented, the development of flavor preferences. There were notable sex differences in the mechanisms for this potentiation. Specifically, in male mice, AgRP neuron activity increased flavor consumption during FNL training, thereby strengthening the association between flavors and nutrients. In female mice, AgRP neuron activity enhanced flavor-nutrient preferences independently of consumption during training, suggesting that AgRP neuron activity enhances the reward value of the nutrient-paired flavor. Finally, in vivo neural activity analyses demonstrated that acute AgRP neuron dynamics track the association between flavors and nutrients in both sexes. Conclusions: Overall, these data (1) demonstrate that AgRP neuron activity enhances associations between flavors and nutrients in a sex-dependent manner and (2) reveal that AgRP neurons track and rapidly update these associations. Taken together, our findings provide new insight into the role of AgRP neurons in assimilating sensory and nutritive signals for food reinforcement

Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise

Objective: Hypothalamic Pro-opiomelanocortin (POMC) and Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons are critical nodes of a circuit within the brain that sense key metabolic cues as well as regulate metabolism. Importantly, these neurons retain an innate ability to rapidly reorganize synaptic inputs and electrophysiological properties in response to metabolic state. While the cellular properties of these neurons have been investigated in the context of obesity, much less is known about the effects of exercise training. Methods: In order to further investigate this issue, we utilized neuron-specific transgenic mouse models to identify POMC and NPY/AgRP neurons for patch-clamp electrophysiology experiments. Results: Using whole-cell patch-clamp electrophysiology, we found exercise depolarized and increased firing rate of arcuate POMC neurons. The increased excitability of POMC neurons was concomitant with increased excitatory inputs to these neurons. In agreement with recent work suggesting leptin plays an important role in the synaptic (re)organization of POMC neurons, POMC neurons which express leptin receptors were more sensitive to exercise-induced changes in biophysical properties. Opposite to effects observed in POMC neurons, NPY neurons were shunted toward inhibition following exercise. Conclusions: Together, these data support a rapid reorganization of synaptic inputs and biophysical properties in response to exercise, which may facilitate adaptations to altered energy balance and glucose metabolism. Keywords: Melanocortin, Energy balance, Leptin receptor, Exercise, Patch-clamp, Electrophysiolog