TNFα drives mitochondrial stress in POMC neurons in obesity

Yi, Chun-Xia; Walter, Marc; Gao, Yuanqing; Pitra, Soledad; Legutko, Beata; Kälin, Stefanie; Layritz, Clarita; García‐Cáceres, Cristina; Bielohuby, Maximilian; Bidlingmaier, Martin; Woods, Stephen C.; Ghanem, Alexander; Conzelmann, Karl‐Klaus; Stern, Javier E.; Jastroch, Martin; Tschöp, Matthias H.

doi:10.1038/ncomms15143

Cited by 91 publications

(120 citation statements)

References 23 publications

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“…To examine potential alterations in mitochondrial morphology in AIF-deficient POMC neurons, mitochondrial architecture and morphology were analyzed via electron microscopy in POMC neurons from AIF ΔPOMC and control mice both upon NCD- and HFD-feeding conditions (Figure S4A). In line with previous reports (Diano et al, 2011; Schneeberger et al, 2013; Yi et al, 2017), mitochondrial architecture in control animals was altered upon HFD feeding with an increase in mitochondrial area (Figure S4B) and perimeter (Figure S4C), a decrease in maximal cristae width (Figure S4D), and a tendency to decreased mitochondrial-ER contacts (Figure S4F). However, these alterations were attenuated upon AIF deletion in POMC neurons in HFD-fed mice.…”

Section: Resultssupporting

confidence: 92%

“…This study revealed not only enhanced TNF-α expression in the mediobasal hypothalamus in DIO mice, but further demonstrated that TNF-α enhances mitochondrial OXPHOS and complex I expression in POMC neurons alongside with mitochondrial enlargement and increased expression of the mitochondrial fusion factor optic atrophy 1 (Opa1) (Yi et al, 2017). Accordingly, ablation of TNF-α signaling in the mediobasal hypothalamus (MBH) of DIO mice reversed diet-induced alterations in mitochondrial dynamics in POMC neurons and improved energy and glucose homeostasis.…”

Section: Discussionmentioning

confidence: 63%

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Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

et al. 2018

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SUMMARY 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.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 63%

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

et al. 2018

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“…; Yi et al . ). However, in a ROI including the PVN visualized by the mEGFP in Sim1 neurons, the abundance of Iba1 did not increase in the PVN of male Sim1‐Cre:Rosa‐mEGFP mice exposed to HF diet (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…; Dorfman and Thaler ; Yi et al . ). Female rodents exposed to HF diet, while having less severe adverse metabolic consequences than male mice, nevertheless develop obesity.…”

Section: Discussionmentioning

confidence: 97%

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Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Nyamugenda

Trentzsch

Russell

et al. 2019

Journal of Neurochemistry

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The hypothalamus is essential for regulation of energy homeostasis and metabolism. Feeding hypercaloric, high‐fat (HF) diet induces hypothalamic arcuate nucleus injury and alters metabolism more severely in male than in female mice. The site(s) and extent of hypothalamic injury in male and female mice are not completely understood. In the paraventricular nucleus (PVN) of the hypothalamus, single‐minded family basic helix‐loop helix transcription factor 1 (Sim1) neurons are essential to control energy homeostasis. We tested the hypothesis that exposure to HF diet induces injury to Sim1 neurons in the PVN of male and female mice. Mice expressing membrane‐bound enhanced green fluorescent protein (mEGFP) in Sim1 neurons (Sim1‐Cre:Rosa‐mEGFP mice) were generated to visualize the effects of exposure to HF diet on these neurons. Male and female Sim1‐Cre:Rosa‐mEGFP mice exposed to HF diet had increased weight, hyperleptinemia, and developed hepatosteatosis. In male and female mice exposed to HF diet, expression of mEGFP was reduced by > 40% in Sim1 neurons of the PVN, an effect paralleled by cell apoptosis and neuronal loss, but not by microgliosis. In the arcuate nucleus of the Sim1‐Cre:Rosa‐mEGFP male mice, there was decreased alpha‐melanocyte‐stimulating hormone in proopiomelanocortin neurons projecting to the PVN, with increased cell apoptosis, neuronal loss, and microgliosis. These defects were undetectable in the arcuate nucleus of female mice exposed to the HF diet. Thus, injury to Sim1 neurons of the PVN is a shared feature of exposure to HF diet in mice of both sexes, while injury to proopiomelanocortin neurons in arcuate nucleus is specific to male mice. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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Type 1 melanocortin receptors in pro‐opiomelanocortin‐, vasopressin‐, and oxytocin‐immunopositive neurons in different areas of mouse brain

Романова

Mikhailova

Mikhrina

et al. 2022

The Anatomical Record

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Information on the localization of the Type 1 melanocortin receptors (MC1Rs) in different regions of the brain is very scarce. As a result, the role of MC1Rs in the functioning of brain neurons and in the central regulation of physiological functions has not been studied. This work aimed to study the expression and distribution of MС1Rs in different brain areas of female C57Bl/6J mice. Using real‐time polymerase chain reaction, we demonstrated the Mс1R gene expression in the cerebral cortex, midbrain, hypothalamus, medulla oblongata, and hippocampus. Using an immunohistochemical approach, we showed the MС1R localization in neurons of the hypothalamic arcuate, paraventricular and supraoptic nuclei, nucleus tractus solitarius (NTS), dorsal hippocampus, substantia nigra, and cerebral cortex. Using double immunolabeling, the MC1Rs were visualized on the surface and in the bodies and outgrowths of pro‐opiomelanocortin (POMC)‐immunopositive neurons in the hypothalamic arcuate nucleus, NTS, hippocampal CA3 and CA1 regions, and cerebral cortex. Co‐localization with POMC indicates that MC1R, like MC3R, is able to function as an autoreceptor. In the paraventricular and supraoptic nuclei, MC1Rs were visualized on the surface and in the cell bodies of vasopressin‐ and oxytocin‐immunopositive neurons, indicating a relationship between hypothalamic MC1R signaling and vasopressin and oxytocin production. The data obtained indicate a wide distribution of MC1Rs in different areas of the mouse brain and their localization in POMC‐, vasopressin‐ and oxytocin‐immunopositive neurons, which may indicate the participation of MC1Rs in the control of many physiological processes in the central nervous system.

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TNFα drives mitochondrial stress in POMC neurons in obesity

Cited by 91 publications

References 23 publications

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Type 1 melanocortin receptors in pro‐opiomelanocortin‐, vasopressin‐, and oxytocin‐immunopositive neurons in different areas of mouse brain

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