Timper K, Paeger L, Sánchez-Lasheras C, Varela L, Jais A, Nolte H, Vogt MC, Hausen AC, Heilinger C, Evers N, Pospisilik JA, Penninger JM, Taylor EB, Horvath TL, Kloppenburg P, Brüning JC.
PMID: 30304679 | DOI: 10.1016/j.celrep.2018.09.034
Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC)-expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFΔPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization of fatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formation in POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improved systemic glucose and energy metabolism in obesity.
Yu, H;Rubinstein, M;Low, MJ;
PMID: 35044906 | DOI: 10.7554/eLife.72883
Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential to regulate food intake and energy balance. However, the ontogenetic transcriptional programs that specify the identity and functioning of these neurons are poorly understood. Here, we use single-cell RNA-sequencing (scRNA-seq) to define the transcriptomes characterizing Pomc-expressing cells in the developing hypothalamus and translating ribosome affinity purification with RNA-sequencing (TRAP-seq) to analyze the subsequent translatomes of mature POMC neurons. Our data showed that Pomc-expressing neurons give rise to multiple developmental pathways expressing different levels of Pomc and unique combinations of transcription factors. The predominant cluster, featured by high levels of Pomc and Prdm12 transcripts, represents the canonical arcuate POMC neurons. Additional cell clusters expressing medium or low levels of Pomc mature into different neuronal phenotypes featured by distinct sets of transcription factors, neuropeptides, processing enzymes, cell surface, and nuclear receptors. We conclude that the genetic programs specifying the identity and differentiation of arcuate POMC neurons are diverse and generate a heterogeneous repertoire of neuronal phenotypes early in development that continue to mature postnatally.
Jais A, Paeger L, Sotelo-Hitschfeld T, Bremser S, Prinzensteiner M, Klemm P, Mykytiuk V, Widdershooven PJM, Vesting AJ, Grzelka K, Min�re M, Cremer AL, Xu J, Korotkova T, Lowell BB, Zeilhofer HU, Backes H, Fenselau H, Wunderlich FT, Kloppenburg P, Br�ning JC
PMID: 32302532 | DOI: 10.1016/j.neuron.2020.03.022
Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOCARC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOCARC neurons arborize densely in the ARC and provide inhibitory synaptic input to nearby anorexigenic POMC neurons. Optogenetic activation of PNOCARC neurons in the ARC and their projections to the bed nucleus of the stria terminalis promotes feeding. Selective ablation of these cells promotes the activation of POMC neurons upon HFD exposure, reduces feeding, and protects from obesity, but it does not affect food intake or body weight under normal chow consumption. We characterize PNOCARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia
Ramírez, S;Haddad-Tóvolli, R;Radosevic, M;Toledo, M;Pané, A;Alcolea, D;Ribas, V;Milà-Guasch, M;Pozo, M;Obri, A;Eyre, E;Gómez-Valadés, AG;Chivite, I;Van Eeckhout, T;Zalachoras, I;Altirriba, J;Bauder, C;Imbernón, M;Garrabou, G;Garcia-Ruiz, C;Nogueiras, R;Soto, D;Gasull, X;Sandi, C;Brüning, JC;Fortea, J;Jiménez, A;Fernández-Checa, JC;Claret, M;
PMID: 35108514 | DOI: 10.1016/j.cmet.2021.12.023
Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.
Park S, Aintablian A, Coupe B, Bouret SG
PMID: 32313051 | DOI: 10.1038/s41467-020-15624-y
Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation
Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting
Biglari, N;Gaziano, I;Schumacher, J;Radermacher, J;Paeger, L;Klemm, P;Chen, W;Corneliussen, S;Wunderlich, CM;Sue, M;Vollmar, S;Klöckener, T;Sotelo-Hitschfeld, T;Abbasloo, A;Edenhofer, F;Reimann, F;Gribble, FM;Fenselau, H;Kloppenburg, P;Wunderlich, FT;Brüning, JC;
PMID: 34002087 | DOI: 10.1038/s41593-021-00854-0
Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of metabolic homeostasis. Electrophysiological and single-cell sequencing experiments have revealed a remarkable degree of heterogeneity of these neurons. However, the exact molecular basis and functional consequences of this heterogeneity have not yet been addressed. Here, we have developed new mouse models in which intersectional Cre/Dre-dependent recombination allowed for successful labeling, translational profiling and functional characterization of distinct POMC neurons expressing the leptin receptor (Lepr) and glucagon like peptide 1 receptor (Glp1r). Our experiments reveal that POMCLepr+ and POMCGlp1r+ neurons represent largely nonoverlapping subpopulations with distinct basic electrophysiological properties. They exhibit a specific anatomical distribution within the arcuate nucleus and differentially express receptors for energy-state communicating hormones and neurotransmitters. Finally, we identify a differential ability of these subpopulations to suppress feeding. Collectively, we reveal a notably distinct functional microarchitecture of critical metabolism-regulatory neurons.
Shi, Z;Stornetta, DS;Stornetta, RL;Brooks, VL;
PMID: 34937769 | DOI: 10.1523/ENEURO.0404-21.2021
The arcuate nucleus (ArcN) is an integrative hub for the regulation of energy balance, reproduction, and arterial pressure (AP), all of which are influenced by Angiotensin II (AngII); however, the cellular mechanisms and downstream neurocircuitry are unclear. Here we show that ArcN AngII increases AP in female rats via two phases, both of which are mediated via activation of AngII type 1 receptors (AT1aR): initial vasopressin-induced vasoconstriction, followed by slowly developing increases in sympathetic nerve activity (SNA) and heart rate (HR). In male rats, ArcN AngII evoked a similarly slow increase in SNA, but the initial pressor response was variable. In females, the effects of ArcN AngII varied during the estrus cycle, with significant increases in SNA, HR, and AP occurring during diestrus and estrus, but only increased AP during proestrus. Pregnancy markedly increased the expression of AT1aR in the ArcN with parallel substantial AngII-induced increases in SNA and MAP. In both sexes, the sympathoexcitation relied on suppression of tonic ArcN sympathoinhibitory Neuropeptide Y inputs, and activation of pro-opiomelanocortin (POMC) projections, to the paraventricular nucleus (PVN). Few or no NPY or POMC neurons expressed the AT1aR, suggesting that AngII increases AP and SNA at least in part indirectly via local interneurons, which express tyrosine hydroxylase (TH) and VGat (i.e. GABAergic). ArcN TH neurons release GABA locally, and central AT1aR and TH neurons mediate stress responses; therefore, we propose that TH AT1aR neurons are well situated to locally coordinate the regulation of multiple modalities within the ArcN in response to stress.SIGNIFICANCEThe arcuate nucleus (ArcN) is an integrative hub for the regulation of energy balance, reproduction, and arterial pressure (AP), all of which are influenced by Angiotensin II (AngII). Here we show that ArcN AngII activates AT1aR to increase AP in male and female rats by slowly increasing sympathetic nerve activity. In females, ArcN AngII also evoked an initial pressor response mediated by vasopressin-induced vasoconstriction. Pregnant and estrus females responded more than males, in association with higher ArcN AT1aR expression. AT1aR were identified in ArcN interneurons that express tyrosine hydroxylase (TH) and GABA. Since brain AT1aR and TH mediate stress responses, ArcN AT1aR TH neurons are well situated to locally coordinate autonomic, hormonal, and behavioral responses to stress.
The Mesencephalic Trigeminal Nucleus Controls Food Intake and Body Weight via Hindbrain POMC Projections
Fortin, SM;Chen, J;Grill, HJ;Hayes, MR;
PMID: 34068091 | DOI: 10.3390/nu13051642
The mesencephalic trigeminal nucleus (Mes5) processes oral sensory-motor information, but its role in the control of energy balance remains unexplored. Here, using fluorescent in situ hybridization, we show that the Mes5 expresses the melanocortin-4 receptor. Consistent with MC4R activation in other areas of the brain, we found that Mes5 microinjection of the MC4R agonist melanotan-II (MTII) suppresses food intake and body weight in the mouse. Furthermore, NTS POMC-projecting neurons to the Mes5 can be chemogenetically activated to drive a suppression in food intake. Taken together, these findings highlight the Mes5 as a novel target of melanocortinergic control of food intake and body weight regulation, although elucidating the endogenous role of this circuit requires future study. While we observed the sufficiency of Mes5 MC4Rs for food intake and body weight suppression, these receptors do not appear to be necessary for food intake or body weight control. Collectively, the data presented here support the functional relevance of the NTS POMC to Mes5 projection pathway as a novel circuit that can be targeted to modulate food intake and body weight.
Ratner C, He Z, Grunddal KV, Skov LJ, Hartmann B, Zhang F, Feuchtinger A, Bjerregaard A, Christoffersen C, Tschöp MH, Finan B, DiMarchi RD, Leinninger GM, Williams KW, Clemmensen C, Holst B.
PMID: 30936142 | DOI: 10.2337/db18-1009
Neurotensin, a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo Here, we demonstrate that a long acting, pegylated analogue of the neurotensin peptide (P-NT) reduces food intake, body weight and adiposity in diet-induced obese (DIO) mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the GLP-1 mimetic liraglutide the two peptides synergized to reduce food intake and body weight relative to each mono-therapy, without inducing a taste aversion. Further, P-NT and liraglutide co-administration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination-therapy. Overall, our data suggest that P-NT and liraglutide combination-therapy could be an enhanced treatment for obesity with improved tolerability compared to liraglutide mono-therapy.
Zhang, Q;Tang, Q;Purohit, NM;Davenport, JB;Brennan, C;Patel, RK;Godschall, E;Zwiefel, LS;Spano, A;Campbell, JN;Güler, AD;
PMID: 36450244 | DOI: 10.1016/j.celrep.2022.111718
Obesity comorbidities such as diabetes and cardiovascular disease are pressing public health concerns. Overconsumption of calories leads to weight gain; however, neural mechanisms underlying excessive food consumption are poorly understood. Here, we demonstrate that dopamine receptor D1 (Drd1) expressed in the agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons of the arcuate hypothalamus is required for appropriate responses to a high-fat diet (HFD). Stimulation of Drd1 and AgRP/NPY co-expressing arcuate neurons is sufficient to induce voracious feeding. Delivery of a HFD after food deprivation acutely induces dopamine (DA) release in the ARC, whereas animals that lack Drd1 expression in ARCAgRP/NPY neurons (Drd1AgRP-KO) exhibit attenuated foraging and refeeding of HFD. These results define a role for the DA input to the ARC that encodes acute responses to food and position Drd1 signaling in the ARCAgRP/NPY neurons as an integrator of the hedonic and homeostatic neuronal feeding circuits.
Porniece Kumar, M;Cremer, AL;Klemm, P;Steuernagel, L;Sundaram, S;Jais, A;Hausen, AC;Tao, J;Secher, A;Pedersen, TÅ;Schwaninger, M;Wunderlich, FT;Lowell, BB;Backes, H;Brüning, JC;
PMID: 34931084 | DOI: 10.1038/s42255-021-00499-0
Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.
González-García, I;García-Clavé, E;Cebrian-Serrano, A;Le Thuc, O;Contreras, RE;Xu, Y;Gruber, T;Schriever, SC;Legutko, B;Lintelmann, J;Adamski, J;Wurst, W;Müller, TD;Woods, SC;Pfluger, PT;Tschöp, MH;Fisette, A;García-Cáceres, C;
PMID: 36889283 | DOI: 10.1016/j.cmet.2023.02.004
Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (d1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, d1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct d1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via d1, thereby contributing to the sexual dimorphism in diet-induced obesity.
