Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance

Gavini, Chaitanya K.; Cook, Tyler; Rademacher, David J.; Mansuy‐Aubert, Virginie

doi:10.1101/793000

Cited by 3 publications

(17 citation statements)

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“…RNAscope in situ hybridization was performed as previously described ( Domi et al, 2019 ; Gavini et al, 2020 ). The RNAscope assay was performed on formalin-fixed, paraffin-embedded (FFPE) tissue.…”

Section: Methodsmentioning

confidence: 99%

Effects of Embryonic Inflammation and Adolescent Psychosocial Environment on Cognition and Hippocampal Staufen in Middle-Aged Mice

Zhang

et al. 2020

Front. Aging Neurosci.

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Accumulating evidence has indicated that embryonic inflammation could accelerate age-associated cognitive impairment, which can be attributed to dysregulation of synaptic plasticity-associated proteins, such as RNA-binding proteins (RBPs). Staufen is a double-stranded RBP that plays a critical role in the modulation of synaptic plasticity and memory. However, relatively few studies have investigated how embryonic inflammation affects cognition and neurobiology during aging, or how the adolescent psychosocial environment affects inflammation-induced remote cognitive impairment. Consequently, the aim of this study was to investigate whether these adverse factors can induce changes in Staufen expression, and whether these changes are correlated with cognitive impairment. In our study, CD-1 mice were administered lipopolysaccharides (LPS, 50 µg/kg) or an equal amount of saline (control) intraperitoneally during days 15-17 of gestation. At 2 months of age, male offspring were randomly exposed to stress (S), an enriched environment (E), or not treated (CON) and then assigned to five groups: LPS, LPS+S, LPS+E, CON, and CON+S. Mice were evaluated at 3-month-old (young) and 15-month-old (middle-aged). Cognitive function was assessed using the Morris water maze test, while Staufen expression was examined at both the protein and mRNA level using immunohistochemistry/western blotting and RNAscope technology, respectively. The results showed that the middle-aged mice had worse cognitive performance and higher Staufen expression than young mice. Embryonic inflammation induced cognitive impairment and increased Staufen expression in the middle-aged mice, whereas adolescent stress/an enriched environment would accelerated/mitigated these effects. Meanwhile, Staufen expression was closely correlated with cognitive performance. Our findings suggested embryonic inflammation can accelerate age-associated learning and memory impairments, and these effects may be related to the Staufen expression.

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Section: Methodsmentioning

confidence: 99%

Effects of Embryonic Inflammation and Adolescent Psychosocial Environment on Cognition and Hippocampal Staufen in Middle-Aged Mice

Zhang

et al. 2020

Front. Aging Neurosci.

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Section: Resultsmentioning

confidence: 99%

“…Using RNAscope, we previously showed the presence of C2CD5 mRNA in many parts of the brain, including high expression in the hypothalamus [9]. We also performed further high-resolution immunoelectron microscopy to visualize C2CD5 cellular localization at the protein level [9]. Using immunoprecipitation and mass spectrometry, we showed that C2CD5 is associated with components of mitochondrial membranes and other cellular membranes [9].…”

Section: Resultsmentioning

confidence: 99%

“…We also performed further high-resolution immunoelectron microscopy to visualize C2CD5 cellular localization at the protein level [9]. Using immunoprecipitation and mass spectrometry, we showed that C2CD5 is associated with components of mitochondrial membranes and other cellular membranes [9]. Immunogold labeling of brain tissue showed the presence of C2CD5 within mitochondrial membranes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous whole-body knockout studies showed that loss of C2CD5 induced pronounced obesity by modifying food intake behavior [9]. It is clearly established that hypothalamic neurons regulate body weight homeostasis by controlling food intake [10, 11].…”

Section: Introductionmentioning

confidence: 99%

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Loss of C2 Domain Protein (C2CD5) Alters Hypothalamic Mitochondrial Trafficking, Structure, and Function

et al. 2021

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Introduction: Mitochondria are essential organelles required for several cellular processes ranging from ATP production to cell maintenance. To provide energy, mitochondria are transported to specific cellular areas in need. Mitochondria also need to be recycled. These mechanisms rely heavily on trafficking events. While mechanisms are still unclear, hypothalamic mitochondria are linked to obesity. Methods: We used C2 domain protein 5 (C2CD5, also called C2 domain-containing phosphoprotein [CDP138]) whole-body KO mice primary neuronal cultures and cell lines to perform electron microscopy, live cellular imaging, and oxygen consumption assay to better characterize mitochondrial alteration linked to C2CD5. Results: This study identified that C2CD5 is necessary for proper mitochondrial trafficking, structure, and function in the hypothalamic neurons. We previously reported that mice lacking C2CD5 were obese and displayed reduced functional G-coupled receptor, melanocortin receptor 4 (MC4R) at the surface of hypothalamic neurons. Our data suggest that in neurons, normal MC4R endocytosis/trafficking necessities functional mitochondria. Discussion: Our data show that C2CD5 is a new protein necessary for normal mitochondrial function in the hypothalamus. Its loss alters mitochondrial ultrastructure, localization, and activity within the hypothalamic neurons. C2CD5 may represent a new protein linking hypothalamic dysfunction, mitochondria, and obesity.

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Melanocortin Pathways: Suppressed and Stimulated Melanocortin-4 Receptor (MC4R)

Hainer

Hainerová²,

Kunešová³

et al. 2020

Physiol Res

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Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

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Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance

Abstract: 1 0 Objective: Rates of overweight and obesity epidemic have risen significantly in the past few 1 1

Cited by 3 publications

References 54 publications

Effects of Embryonic Inflammation and Adolescent Psychosocial Environment on Cognition and Hippocampal Staufen in Middle-Aged Mice

Effects of Embryonic Inflammation and Adolescent Psychosocial Environment on Cognition and Hippocampal Staufen in Middle-Aged Mice

Loss of C2 Domain Protein (C2CD5) Alters Hypothalamic Mitochondrial Trafficking, Structure, and Function

Melanocortin Pathways: Suppressed and Stimulated Melanocortin-4 Receptor (MC4R)

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