Featured ArticlesVolume 5 | No. 7 | July 2016
|Autonomous interconversion between adult pancreatic α-cells and β-cellsYe and colleagues establish an efficient and adaptable lineage tracing system for pancreatic cells. The authors quantitatively identify the sources of adult β-cells under multiple metabolic conditions, and propose a kinetic model of cell conversion. Their data also reconcile the discrepant findings generated by the tamoxifen-inducible system.
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Background: Evidence hints at the ability of β-cells to emerge from non-β-cells upon genetic or pharmacological interventions. However, their quantitative contributions to the process of autonomous β-cell regeneration without genetic or pharmacological manipulations remain to be determined.
Methods & Results: Using PANIC-ATTAC mice, a model of titratable, acute β-cell apoptosis capable of autonomous, and effective islet mass regeneration, we demonstrate that an extended washout of residual tamoxifen activity is crucial for β-cell lineage tracing studies using the tamoxifen-inducible Cre/loxP systems. We further establish a doxycycline-inducible system to label different cell types in the mouse pancreas and pursued a highly quantitative assessment to trace adult β-cells after various metabolic challenges. Beyond proliferation of pre-existing β-cells, non-β-cells contribute significantly to the post-challenge regenerated β-cell pool. α-cell trans-differentiation is the predominant mechanism upon post-apoptosis regeneration and multiparity. No contributions from exocrine acinar cells were observed. During diet-induced obesity, about 25% of α-cells arise de novo from β-cells. Ectopic expression of Nkx6.1 promotes α-to-β conversion and insulin production.
Conclusions: We identify the origins and fates of adult β-cells upon post-challenge upon autonomous regeneration of islet mass and establish the quantitative contributions of the different cell types using a lineage tracing system with high temporal resolution.[Hide abstract]
|Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells DiGruccio et al. offer an alternate mechanistic explanation how ghrelin achieves its insulinostatic actions. Their observations underscore that delta cells play an underappreciated but important physiological role in controlling insulin output by local feedback within pancreatic islets. The high quality transcriptomes from delta, beta, and alpha cells that were instrumental in this discovery will be invaluable to unravel the complex crosstalk that tightly balances insulin and glucagon release from healthy islets and breaks down in diabetes.|
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Objective: Complex local crosstalk amongst endocrine cells within the islet ensures tight coordination of their endocrine output. This is illustrated by the recent demonstration that the negative feedback control by delta cells within pancreatic islets determines the homeostatic set-point for plasma glucose during mouse postnatal development. However, the close association of islet endocrine cells that facilitates paracrine crosstalk also complicates the distinction between effects mediated directly on beta cells from indirect effects mediated via local intermediates, such as somatostatin from delta cells.
Methods: To resolve this problem, we generated reporter mice that allow collection of pure pancreatic delta cells along with alpha and beta cells from the same islets and generated comprehensive transcriptomes for each islet endocrine cell type. These transcriptomes afford an unparalleled view of the receptors expressed by delta, alpha and beta cells, and allow the prediction of which signal targets which endocrine cell type with great accuracy.
Results: From these transcriptomes, we discovered that the ghrelin receptor is expressed exclusively by delta cells within the islet, which was confirmed by fluorescent in situ hybridization and qPCR. Indeed, ghrelin increases intracellular calcium in delta cells in intact mouse islets, measured by GCaMP6 and robustly potentiates glucose-stimulated somatostatin secretion on mouse and human islets in both static and perfusion assays. In contrast, des-acyl-ghrelin at the same dose had no effect on somatostatin secretion and did not block the actions of ghrelin.
Conclusions: These results offer a straightforward explanation for the well-known insulinostatic actions of ghrelin. Rather than engaging beta cells directly, ghrelin engages delta cells to promote local inhibitory feedback that attenuates insulin release. These findings illustrate the power of our approach to resolve some of the long-standing conundrums with regard to the rich feedback that occurs within the islet that is integral to islet physiology and therefore highly relevant to diabetes.[Hide abstract]
|PI3 kinases p110α and PI3K-C2β negatively regulate cAMP via PDE3/8 to control insulin secretionThe preservation of nutrient-stimulated insulin secretion is essential for proper glycaemic control, particularly in the face of insulin resistance. Kolic et al. provide new insight into the basis for phosphatidylinositol-3-OH kinase (PI3K)-mediated regulation of insulin secretion in mouse and human islets. PI3K-C2β limits glucose-stimulated insulin secretion (GSIS) by suppressing cAMP responses in a manner that requires phosphodiesterase (PDE) 3 (in humans and mice) and PDE8B (in mice). PI3K inhibition does not augment GSIS in islets from type-2 diabetic donors.
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Objective: Phosphatidylinositol-3-OH kinase (PI3K) signalling in the endocrine pancreas contributes to glycaemic control. However, the mechanism by which PI3K modulates insulin secretion from the pancreatic beta cell is poorly understood. Thus, our objective was two-fold; to determine the signalling pathway by which acute PI3K inhibition enhances glucose-stimulated insulin secretion (GSIS) and to examine the role of this pathway in islets from type-2 diabetic (T2D) donors.
Methods: Isolated islets from mice and non-diabetic or T2D human donors, or INS 832/13 cells, were treated with inhibitors of PI3K and/or phosphodiesterases (PDEs). The expression of PI3K-C2β was knocked down using siRNA. We measured insulin release, single-cell exocytosis, intracellular Ca2+ responses ([Ca2+]i) and Ca2+ channel currents, intracellular cAMP concentrations ([cAMP]i), and activation of cAMP-dependent protein kinase A (PKA) and protein kinase B (PKB/AKT).
Results: The non-specific PI3K inhibitor wortmannin amplifies GSIS, raises [cAMP]i and activates PKA, but is without effect in T2D islets. Direct inhibition of specific PDE isoforms demonstrates a role for PDE3 (in humans and mice) and PDE8 (in mice) downstream of PI3K, and restores glucose-responsiveness of T2D islets. We implicate a role for the Class II PI3K catalytic isoform PI3K-C2β in this effect by limiting beta cell exocytosis.
Conclusions: PI3K limits GSIS via PDE3 in human islets. While inhibition of p110α or PIK-C2β signalling per se, may promote nutrient-stimulated insulin release, we now suggest that this signalling pathway is perturbed in islets from T2D donors.[Hide abstract]
|Lack of AKT in adipocytes causes severe lipodystrophyLipodystrophy is a disease characterized by lack of adipose tissue accompanied by metabolic derangements. Shearin and colleagues delete Akt1 and Akt2 selectively in adipocytes of mice, thus interrupting a critical insulin-signalling pathway. The authors find that loss of these AKT isoforms in adipocytes causes profound lipodystrophy, associated with fatty liver and systemic insulin resistance.|
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Objective: Adipose depot mass is tightly regulated to maintain energy homeostasis. AKT is a critical kinase in the insulin-signaling cascade that is required for the process of adipogenesis in vitro. However, the role of AKT in the maintenance and/or function of mature adipocytes in vivo had not been examined.
Methods: To study this, we deleted Akt1 and Akt2 in adipocytes of mice using the AdipoQ-Cre driver.
Results: Strikingly, mice lacking adipocyte AKT were severely lipodystrophic, having dramatically reduced gonadal adipose and no discernible subcutaneous or brown adipose tissue. As a result, these mice developed severe insulin resistance accompanied by fatty liver, hepatomegaly and with enlarged islets of Langerhans.
Conclusions: These data reveal the critical role of adipocyte AKT and insulin signaling for maintaining adipose tissue mass.[Hide abstract]
|Lipodystrophy in mice with adipose tissue-specific insulin receptor ablationAdipose tissue is a complex organ, playing an active role in whole-body energy and metabolic homeostasis. Qiang and colleagues generate and phenotype a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line. They find that Adipoq-Cre-mediated insulin receptor (IR) knockout (KO) leads to severe lipodystrophy rather than simply reduced fat mass. The lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly (liver, heart, pancreas, kidney, spleen), and impaired adipokine secretion.|
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Objective: Insulin signaling plays pivotal roles in the development and metabolism of many tissues and cell types. A previous study demonstrated that ablation of insulin receptor (IR) with aP2-Cre markedly reduced adipose tissues mass and protected mice from obesity. However, multiple studies have demonstrated widespread non-adipocyte recombination of floxed alleles in aP2-Cre mice. These findings underscore the need to re-evaluate the role of IR in adipocyte and systemic metabolism with a more adipose tissue-specific Cre mouse line.
Methods: We generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line.
Results: Here we show that the Adipoq-Cre-mediated IR KO in mice leads to lipodystrophy and metabolic dysfunction, which is in stark contrast to the previous study. In contrast to white adipocytes, absence of insulin signaling does not affect development of marrow and brown adipocytes, but instead is required for lipid accumulation particularly for the marrow adipocytes. Lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly, and impaired adipokine secretion.
Conclusions: Our results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.[Hide abstract]
|AGPAT2 is essential for postnatal development and maintenance of white and brown adipose tissue Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a lack of adipose tissue (AT). Mutations in the AGPAT2 gene, encoding 1-acylglycerol-3-phosphate O-acyltransferase 2, cause the most common form of CGL. Cautivo et al. show that Agpat2-/- mice are born with AT, which undergoes a rapid degenerative process that leads to the total destruction of AT during the first week after birth. Adipocyte-like cells from differentiated Agpat2-/- mouse embryonic fibroblasts recapitulate the abnormal phenotype observed in subcutaneous white adipose tissue of Agpat2-/- new-born mice. Based on their in vivo and in vitro findings, the authors propose AGPAT2 deficient adipocytes have an impaired capacity to adapt to the massive lipid availability associated with postnatal feeding, leading to cellular stress, death and inflammatory destruction of adipose tissue.|
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Objective: Characterize the cellular and molecular events responsible for lipodystrophy in AGPAT2 deficient mice.
Methods: Adipose tissue and differentiated MEF were assessed using light and electron microscopy, followed by protein (immunoblots) and mRNA analysis (qPCR). Phospholipid profiling was determined by electrospray ionization tandem mass spectrometry (ESI-MS/MS).
Results: In contrast to adult Agpat2−/− mice, fetuses and newborn Agpat2−/− mice have normal mass of white and brown adipose tissue. Loss of both the adipose tissue depots occurs during the first week of postnatal life as a consequence of adipocyte death and inflammatory infiltration of the adipose tissue. At the ultrastructural level, adipose tissue of newborn Agpat2−/− mice is virtually devoid of caveolae and has abnormal mitochondria and lipid droplets. Autophagic structures are also abundant. Consistent with these findings, differentiated Agpat2−/− mouse embryonic fibroblasts (MEFs) also have impaired adipogenesis, characterized by a lower number of lipid-laden cells and ultrastructural abnormalities in lipid droplets, mitochondria and plasma membrane. Overexpression of PPARγ, the master regulator of adipogenesis, increased the number of Agpat2−/− MEFs that differentiated into adipocyte-like cells but did not prevent morphological abnormalities and cell death. Furthermore, differentiated Agpat2−/− MEFs have abnormal phospholipid compositions with 3-fold increased levels of phosphatidic acid.
Conclusions: We conclude that lipodystrophy in Agpat2−/− mice results from postnatal cell death of adipose tissue in association with acute local inflammation. It is possible that AGPAT2 deficient adipocytes have an altered lipid filling or a reduced capacity to adapt the massive lipid availability associated with postnatal feeding.[Hide abstract]
|Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potentialChronic over-nutrition results in low-grade inflammation in metabolically sensitive tissues that contributes to systemic metabolic dysregulation. Johnson, Qin and colleagues report that FATP1 plays a critical role in suppressing inflammation in vitro and reducing Macrophage infiltration and inflammation in vivo through modulation of lipid mediators and oxidative stress. The authors demonstrate for the first time that FATP1 provides a unique mechanism by which the metabolic and inflammatory tone of adipose and systemic metabolism may be regulated.|
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Objective: A novel approach to regulate obesity-associated adipose inflammation may be through metabolic reprogramming of macrophages (MΦs). Broadly speaking, MΦs dependent on glucose are pro-inflammatory, classically activated MΦs (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, MΦs that primarily metabolize fatty acids are alternatively activated MΦs (AAM) and maintain tissue insulin sensitivity. In actuality, there is much flexibility and overlap in the CAM-AAM spectrum in vivo dependent upon various stimuli in the microenvironment. We hypothesized that specific lipid trafficking proteins, e.g. fatty acid transport protein 1 (FATP1), would direct MΦ fatty acid transport and metabolism to limit inflammation and contribute to the maintenance of adipose tissue homeostasis.
Methods: Bone marrow derived MΦs (BMDMs) from Fatp1−/− and Fatp1+/+ mice were used to investigate FATP1-dependent substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. We also generated C57BL/6J chimeric mice by bone marrow transplant specifically lacking hematopoetic FATP1 (Fatp1B-/-) and controls Fatp1B+/+. Mice were challenged by high fat diet (HFD) or low fat diet (LFD) and analyses including MRI, glucose and insulin tolerance tests, flow cytometric, histologic, and protein quantification assays were conducted. Finally, an FATP1-overexpressing RAW 264.7 MΦ cell line (FATP1-OE) and empty vector control (FATP1-EV) were developed as a gain of function model to test effects on substrate metabolism, bioenergetics, metabolomics, and inflammatory responses.
Results: Fatp1 is downregulated with pro-inflammatory stimulation of MΦs. Fatp1−/− BMDMs and FATP1-OE RAW 264.7 MΦs demonstrated that FATP1 reciprocally controled metabolic flexibility, i.e. lipid and glucose metabolism, which was associated with inflammatory response. Supporting our previous work demonstrating the positive relationship between glucose metabolism and inflammation, loss of FATP1 enhanced glucose metabolism and exaggerated the pro-inflammatory CAM phenotype. Fatp1B-/- chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1B+/+ controls. Adipose tissue macrophages displayed a CAM-like phenotype in the absence of Fatp1. Conversely, functional overexpression of FATP1 decreased many aspects of glucose metabolism and diminished CAM-stimulated inflammation in vitro. FATP1 displayed acyl-CoA synthetase activity for long chain fatty acids in MΦs and modulated lipid mediator metabolism in MΦs.
Conclusions: Our findings provide evidence that FATP1 is a novel regulator of MΦ activation through control of substrate metabolism. Absence of FATP1 exacerbated pro-inflammatory activation in vitro and increased local and systemic components of the metabolic syndrome in HFD-fed Fatp1B-/- mice. In contrast, gain of FATP1 activity in MΦs suggested that Fatp1-mediated activation of fatty acids, substrate switch to glucose, oxidative stress, and lipid mediator synthesis are potential mechanisms. We demonstrate for the first time that FATP1 provides a unique mechanism by which the inflammatory tone of adipose and systemic metabolism may be regulated.[Hide abstract]
|G0/G1 Switch Gene 2 controls adipose triglyceride lipase activity and lipid metabolism in skeletal muscleThe first and rate-limiting step of skeletal muscle lipolysis is catalysed by adipose triglyceride lipase (ATGL). The data of Laurens and colleagues show that the protein G0/G1 Switch Gene 2 (G0S2) inhibits ATGL activity in mouse and human skeletal muscle and plays a central role in regulating lipid metabolism and substrate oxidation. These results also suggest that changes in G0S2 expression may cause accumulation of lipotoxic species in skeletal muscle and subsequent impairment of insulin action.|
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Objective: Recent data suggest that adipose triglyceride lipase (ATGL) plays a key role in providing energy substrate from triglyceride pools and that alterations of its expression/activity relate to metabolic disturbances in skeletal muscle. Yet little is known about its regulation. We here investigated the role of the protein G0/G1 Switch Gene 2 (G0S2), recently described as an inhibitor of ATGL in white adipose tissue, in the regulation of lipolysis and oxidative metabolism in skeletal muscle.
Methods: We first examined G0S2 protein expression in relation to metabolic status and muscle characteristics in humans. We next overexpressed and knocked down G0S2 in human primary myotubes to assess its impact on ATGL activity, lipid turnover and oxidative metabolism, and further knocked down G0S2 in vivo in mouse skeletal muscle.
Results: G0S2 protein is increased in skeletal muscle of endurance-trained individuals and correlates with markers of oxidative capacity and lipid content. Recombinant G0S2 protein inhibits ATGL activity by about 40% in lysates of mouse and human skeletal muscle. G0S2 overexpression augments (+49%, p < 0.05) while G0S2 knockdown strongly reduces (−68%, p < 0.001) triglyceride content in human primary myotubes and mouse skeletal muscle. We further show that G0S2 controls lipolysis and fatty acid oxidation in a strictly ATGL-dependent manner. These metabolic adaptations mediated by G0S2 are paralleled by concomitant changes in glucose metabolism through the modulation of Pyruvate Dehydrogenase Kinase 4 (PDK4) expression (5.4 fold, p < 0.001). Importantly, downregulation of G0S2 in vivo in mouse skeletal muscle recapitulates changes in lipid metabolism observed in vitro.
Conclusions: Collectively, these data indicate that G0S2 plays a key role in the regulation of skeletal muscle ATGL activity, lipid content and oxidative metabolism.[Hide abstract]
|Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivityAberrant amino acid metabolism has long been recognized as a feature of obesity and accompanying metabolic disease. White, Lapworth et al. describe the results of a nutritional intervention study in which they restricted branched-chain amino acid (BCAA) dietary supply in Zucker-lean and Zucker-fatty rats, the latter being a model of insulin resistance and impaired BCAA metabolism. Their findings demonstrate a clear cause and effect relationship between BCAA supply and insulin sensitivity and highlight underlying biochemical mechanisms.|
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Objective: A branched-chain amino acid (BCAA)-related metabolic signature is strongly associated with insulin resistance and predictive of incident diabetes and intervention outcomes. To better understand the role that this metabolite cluster plays in obesity-related metabolic dysfunction, we studied the impact of BCAA restriction in a rodent model of obesity in which BCAA metabolism is perturbed in ways that mirror the human condition.
Methods: Zucker-lean rats (ZLR) and Zucker-fatty rats (ZFR) were fed either a custom control, low fat (LF) diet, or an isonitrogenous, isocaloric LF diet in which all three BCAA (Leu, Ile, Val) were reduced by 45% (LF-RES). We performed comprehensive metabolic and physiologic profiling to characterize the effects of BCAA restriction on energy balance, insulin sensitivity, and glucose, lipid and amino acid metabolism.
Results: LF-fed ZFR had higher levels of circulating BCAA and lower levels of glycine compared to LF-fed ZLR. Feeding ZFR with the LF-RES diet lowered circulating BCAA to levels found in LF-fed ZLR. Activity of the rate limiting enzyme in the BCAA catabolic pathway, branched chain keto acid dehydrogenase (BCKDH), was lower in liver but higher in skeletal muscle of ZFR compared to ZLR and was not responsive to diet in either tissue. BCAA restriction had very little impact on metabolites studied in liver of ZFR where BCAA content was low, and BCKDH activity was suppressed. However, in skeletal muscle of LF-fed ZFR compared to LF-fed ZLR, where BCAA content and BCKDH activity were increased, accumulation of fatty acyl CoAs was completely normalized by dietary BCAA restriction. BCAA restriction also normalized skeletal muscle glycine content and increased urinary acetyl glycine excretion in ZFR. These effects were accompanied by lower RER and improved skeletal muscle insulin sensitivity in LF-RES fed ZFR as measured by hyperinsulinemic-isoglycemic clamp.
Conclusions: Our data are consistent with a model wherein elevated circulating BCAA contribute to development of obesity-related insulin resistance by interfering with lipid oxidation in skeletal muscle. BCAA-dependent lowering of the skeletal muscle glycine pool appears to contribute to this effect by slowing acyl-glycine export to the urine.[Hide abstract]
|Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4Glucagon-like peptide-1 (GLP-1) based drugs are one of the leading treatment options for obesity and diabetes. Lee and colleagues propose that glucocorticoid counteracts the anorexigenic effects of GLP-1R agonist treatment. Their findings with low dose dexamethasone and lesion approaches support the novel concept that the potency of Exendin-4 as an anorexigenic drug is inversely related to glucocorticoid secretion. Therefore, manipulating glucocorticoid receptor mechanisms will be of interest for the future design of GLP-1-based therapies.|
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Objective: Glucagon-like peptide-1 (GLP-1) analogs are attractive options for the treatment of type II diabetes and obesity because of their incretin and anorexigenic effects. Peripheral administration of the GLP-1R agonist Exendin-4 (Ex-4) also increases glucocorticoid secretion in rodents and humans, but whether the released glucocorticoids interact with Ex-4's anorexigenic effect remains unclear.
Methods: To test this, we used two experimental approaches that suppress corticosterone secretion and then assessed Ex-4 effects on eating in adult male rats. First, we combined acute and chronic low dose dexamethasone treatment with Ex-4. Second, we ablated hindbrain catecholamine neurons projecting to the hypothalamus with anti-dopamine-β-hydroxylase-saporin (DSAP) to block Ex-4-induced corticosterone secretion.
Results: Combining dexamethasone and Ex-4 produced a larger acute anorexigenic effect than Ex-4 alone. Likewise, chronic dexamethasone and Ex-4 co-treatment produced a synergistic effect on eating and greater body weight loss in diet-induced obese rats than Ex-4 alone. DSAP lesions not only blunted Ex-4's ability to increase corticosterone secretion, but potentiated the anorexigenic effect of Ex-4, indicating that Ex-4-dependent corticosterone secretion opposes Ex-4's actions. Consistent with the enhancement of Ex-4's anorexigenic effect, DSAP lesion altered Ex-4-dependent changes in neuropeptide Y, preproglucagon, and corticotropin releasing hormone gene expression involved in glucocorticoid feedback.
Conclusions: Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies.[Hide abstract]
|Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responsesThe melanocortin-3 receptor (MC3R) is expressed in hypothalamic and limbic structures controlling autonomic function and complex ingestive behaviours. Mavrikaki and colleagues find that MC3Rs are required for the full expression of feeding-related motivational responses, but only in situations of caloric insufficiency. The authors also report that rescuing MC3Rs in the mesolimbic dopaminergic system enhances some feeding-related motivational responses during situations of caloric insufficiency, but has no impact on the obese phenotype.|
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Objective: Appetitive responses to weight loss are mediated by a nutrient-sensing neural network comprised of melanocortin neurons. The role of neural melanocortin-3 receptors (MC3R) in mediating these responses is enigmatic. Mc3r knockout mice exhibit a paradoxical phenotype of obesity and reduced feeding-related behaviors in situations of nutrient scarcity. Here we examined whether MC3Rs expressed in mesolimbic neurons regulate feeding-related motivational responses.
Methods: Interactions between Mc3r genotype, cognitive function and energy balance on food self-administration were assessed using operant conditioning with fixed- and progressive ratio (FR1/PR1) settings. Inhibition of Mc3r transcription by a loxP-flanked transcriptional blocker (TB) in C57BL/6JN mice (Mc3rTB/TB) was reversed in mesolimbic neurons using DAT-Cre (DAT-MC3R).
Results: Caloric restriction (CR) caused 10–15% weight loss and increased motivation to acquire food rewards during training sessions. c-Fos-expression in the nucleus accumbens was increased 1 h following food presentation. While exhibiting weight loss, total food self-administration, enhanced motivation to self-administer food rewards in training sessions held during CR and c-Fos-activation in the nucleus accumbens following re-feeding were all markedly attenuated in Mc3rTB/TB mice. In contrast, cognitive abilities were normal in Mc3rTB/TB mice. Total food self-administration during FR1 sessions was not rescued in DAT-MC3R mice, however enhanced motivational responses to self-administer food rewards in PR1 conditions were restored. The nutrient-partitioning phenotype observed with Mc3r-deficiency was not rescued in DAT-MC3R mice.
Conclusions: Mesolimbic MC3Rs mediate enhanced motivational responses during CR. However, they are insufficient to restore normal caloric loading when food is presented during CR and do not affect metabolic conditions altering nutrient partitioning.[Hide abstract]
|PGC-1α expression in murine AgRP neurons regulates food intake and energy balanceThe transcriptional coactivator PGC-1α is one of the key regulators of cellular energy homeostasis and strongly affects mitochondrial biogenesis and oxidative metabolism. Gill et al. demonstrate that PGC-1α is directly involved in the regulation of feeding, activity, and body temperature by modulating the activity of agouti-related protein (AgRP) neurons. These changes are associated with an increase in fat and a decrease in lean mass. Importantly, for the first time, the role of PGC-1α in the regulation of appetite can be dissociated from confounding effects of knockout of PGC-1α in peripheral tissues and in other areas of the brain.
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Objective: Food intake and whole-body energy homeostasis are controlled by agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus of the hypothalamus. Key energy sensors, such as the AMP-activated protein kinase (AMPK) or sirtuin 1 (SIRT1), are essential in AgRP and POMC cells to ensure proper energy balance. In peripheral tissues, the transcriptional coactivator PGC-1α closely associates with these sensors to regulate cellular metabolism. The role of PGC-1α in the ARC nucleus, however, remains unknown.
Methods: Using AgRP and POMC neurons specific knockout (KO) mouse models we studied the consequences of PGC-1α deletion on metabolic parameters during fed and fasted states and on ghrelin and leptin responses. We also took advantage of an immortalized AgRP cell line to assess the impact of PGC-1α modulation on fasting induced AgRP expression.
Results: PGC-1α is dispensable for POMC functions in both fed and fasted states. In stark contrast, mice carrying a specific deletion of PGC-1α in AgRP neurons display increased adiposity concomitant with significantly lower body temperature and RER values during nighttime. In addition, the absence of PGC-1α in AgRP neurons reduces food intake in the fed and fasted states and alters the response to leptin. Finally, both in vivo and in an immortalized AgRP cell line, PGC-1α modulates AgRP expression induction upon fasting.
Conclusions: Collectively, our results highlight a role for PGC-1α in the regulation of AgRP neuronal functions in the control of food intake and peripheral metabolism.[Hide abstract]