The AgRP-expressing neurons in the arcuate nucleus drive food-seeking behaviours during caloric restriction; a mouse study of monosynaptic retrograde rabies spread and optogenetic circuit mapping reveals that these neurons are activated by input from hypothalamic paraventricular nucleus cells and their activation or inhibition can modulate feeding behaviour. Increasing activity of the AgRP neurons in the hypothalamus drives food-seeking behaviours during periods of calorie restriction. The source of the input that provokes this hunger response was unknown. Bradford Lowell and colleagues have now mapped the inputs into these AgRP neurons and demonstrate that the paraventricular nucleus, normally thought of as a satiety centre, contains orexigenic neurons that drive AgRP neurons and food-seeking in mice, even when the mouse was otherwise sated. This work establishes specific populations of paraventricular nucleus neurons as drivers of a powerful hub within the feeding circuit. Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake1,2,3,4,5. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding3,6,7. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity8,9,10. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

Rationale:: Decreased fatty acid oxidation (FAO) with increased reliance on glucose are hallmarks of metabolic remodeling that occurs in pathological cardiac hypertrophy and is associated with decreased myocardial energetics and impaired cardiac function. To date, it has not been tested whether prevention of the metabolic switch that occurs during the development of cardiac hypertrophy has unequivocal benefits on cardiac function and energetics. Objective:: Because malonyl CoA production via acetyl CoA carboxylase 2 (ACC2) inhibits the entry of long chain fatty acids into the mitochondria, we hypothesized that mice with a cardiac-specific deletion of ACC2 (ACC2H ^−/− ) would maintain cardiac FAO and improve function and energetics during the development of pressure-overload hypertrophy. Methods and Results:: ACC2 deletion led to a significant reduction in cardiac malonyl CoA levels. In isolated perfused heart experiments, left ventricular function and oxygen consumption were similar in ACC2H ^−/− mice despite an ≈60% increase in FAO compared with controls (CON). After 8 weeks of pressure overload via transverse aortic constriction (TAC), ACC2H ^−/− mice exhibited a substrate utilization profile similar to sham animals, whereas CON-TAC hearts had decreased FAO with increased glycolysis and anaplerosis. Myocardial energetics, assessed by ³¹ P nuclear magnetic resonance spectroscopy, and cardiac function were maintained in ACC2H ^−/− after 8 weeks of TAC. Furthermore, ACC2H ^−/− -TAC demonstrated an attenuation of cardiac hypertrophy with a significant reduction in fibrosis relative to CON-TAC. Conclusions:: These data suggest that reversion to the fetal metabolic profile in chronic pathological hypertrophy is associated with impaired myocardial function and energetics and maintenance of the inherent cardiac metabolic profile and mitochondrial oxidative capacity is a viable therapeutic strategy.

Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1)⁺ neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1⁺ neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1⁺, located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs. Significance Both in rodents and humans, melanocortin-4 receptors (MC4Rs) suppress appetite and prevent obesity. Unfortunately, the underlying neural mechanisms by which MC4Rs regulate food intake are poorly understood. Unraveling these mechanisms may open up avenues for treating obesity. In the present study we have established that MC4Rs on neurons in the paraventricular nucleus of the hypothalamus are both necessary and sufficient for MC4R control of feeding and that these neurons are glutamatergic and not GABAergic and do not express the neuropeptides oxytocin, corticotropin-releasing hormone, prodynorphin, or vasopressin. In addition, we identify downstream projections from these glutamatergic neurons to the lateral parabrachial nucleus, which could mediate the appetite suppressing effects.