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Identification of adipose tissue metabolic memory of anorexia nervosa

ABSTRACT: Anorexia nervosa (AN) is a complex debilitating disease characterized by intense fear of weight gain and excessive exercise. It is the deadliest of any psychiatric disorder with a high rate of recidivism, yet its pathophysiology is unclear. The Activity-Based Anorexia (ABA) paradigm is a widely accepted mouse model of AN that recapitulates hypophagia and hyperactivity despite reduced body weight, however, not the chronicity. Here, we modified the prototypical ABA paradigm to increase the time to lose 25% of baseline body weight from less than 7 days to more than 2 weeks. We used this paradigm to identify persistently altered genes after weight restoration that represent a metabolic memory of under-nutrition and may contribute to AN relapse. We focused on adipose tissue as it was identified as a major location of metabolic memory of over-nutririon. We identified 300 persistently dysregulated genes, including Calm2 and Vps13d, which could be potential global regulators of metabolic memory in both chronic over- and under-nutrition. However, despite being on the opposite spectrum of weight perturbations, the majority of metabolic memory genes of under- and over-nutrition do not overlap, suggestive of the different mechanisms involved in these extreme nutritional statuses.

ORGANISM(S): Mus musculus

PROVIDER: GSE229316 | GEO | 2023/08/23

REPOSITORIES: GEO

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Placental miR-340 mediates vulnerability to activity based anorexia in mice

Project description:Anorexia nervosa (AN) is a devastating eating disorder characterized by self-starvation that mainly affects women. Its etiology is unknown, which impedes successful treatment options leading to a limited chance of full recovery. Here, we show that gestation is a vulnerable window that can influence the predisposition to AN. By screening placental microRNA expression of naive and prenatally stressed (PNS) fetuses and assessing vulnerability to activity-based anorexia (ABA) in early adulthood, we identify miR-340 as a sexually dimorphic regulator involved in prenatal programming of ABA. PNS caused gene-body hypermethylation of placental miR-340, which is associated with reduced miR-340 expression and increased protein levels of several target transcripts; Gr, Cry2 and H3F3b. MiR-340 is linked to the expression of several nutrient transporters both in mice and human placentas. Using placenta-specific lentiviral transgenes and embryo transfer, we demonstrate the key role miR-340 plays in the mechanism involved in early life programming of ABA.

2018-03-27 | GSE110597 | GEO

Targeting hepatic IRE1a for Treating GDF15-driven Anorexia in Chemotherapy

Project description:Anorexia and other side effects of chemotherapy significantly limit the clinical applications of these chemotherapeutic agents, with underlying mechanisms still unclear. A growing body of research reveals that elevated levels of circulating GDF15 after chemotherapy are essential in initiating anorexia and other side effects by activating GFRAL+ neurons in the brainstem. However, the full array of context-dependent transcriptional regulators controlling Gdf15 expression remains to be defined. This study reports that chemotherapy drugs acutely stimulate liver GDF15 production via selective activation of the hepatic stress sensor IRE1α, thereby controlling circulating GDF15 levels. Genetic ablation of hepatic IRE1α reduces circulating GDF15 and alleviates anorexia and body weight loss following chemotherapy drug treatments in tumor-bearing mice. Mechanistically, chemotherapy drugs activate hepatic IRE1α RNase activity to produce the active form of the transcription factor XBP1 to promotes the expression of Gdf15 gene in hepatocytes. Moreover, treatment with pharmacological IRE1α RNase inhibitor effectively suppresses liver Gdf15 expression and circulating GDF15 levels, resulting in improvements in chemotherapy-induced anorexia and body weight loss. Our results reveal a stress-responsive mechanism that mediates communication between the liver and brain. This mechanism can be targeted pharmacologically to alleviate anorexic side effects that accompany chemotherapy-induced body weight loss.

2024-04-22 | GSE235695 | GEO

Distinct transcriptional responses across tissue-resident macrophages to short-term and long-term metabolic challenge

Project description:The innate immune system safeguards the organism from both pathogenic and environmental stressors. Even physiological levels of nutrients affect organismal and intra-cellular metabolism and challenge the immune system. In the long term, over-nutrition leads to low-grade systemic inflammation. Here, we investigate tissue-resident components of the innate immune-system –macrophages and their response to short-term and long-term nutritional challenges. We analyze the transcriptomes of seven tissue-resident macrophage populations upon metabolic challenge and identify adipose tissue macrophages and the IL-1 pathway as early sensors of metabolic changes. Furthermore, by comparing functional responses between macrophage subtypes, we propose a regulatory, anti-inflammatory role of heat shock proteins of the HSP70 family in response to a metabolic challenge. Our data provides a resource for assessing the impact of nutrition and over-nutrition on the spectrum of macrophages across tissues with a potential for identification of systemic responses.

2020-02-04 | GSE133127 | GEO

Hypothalamic responses to reduced food intake in healthy animals and rats bearing small tumors

Project description:Anorexia is frequently observed during cancer and associated with increased morbidity and mortality. Our previous work has shown the presence of transcription factors in the hypothalamus of anorectic tumor-bearing rats. The aim of the present study was, therefore, to assess expression of neuropeptides, neurotransmitter-synthesizing enzymes and receptors in this structure. Morris hepatoma 7777 cells injected subcutaneously in Buffalo rats provoked a 15% reduction in food intake and 10% lower body weight when the tumor represented 1-2% of body mass. Real-time PCR showed that tumor-bearing rats did not display the increase in hypothalamic agouti-related peptide mRNA observed in food-restricted weight-matched animals. These findings indicate that blunted hypothalamic AgRp mRNA expression underlies cancer-associated anorexia.

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SAPS3 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge

Project description:Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanism underneath that is not clear. Here, we demonstrate serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is an essential negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Remarkably, either whole-body or liver-specific deletion of SAPS3 protects mice against the HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout mice under HFD. Together, our results reveal that SAPS3 is a critical negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes.

2023-01-18 | GSE210333 | GEO

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Project description:Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. The goal of this study is to isolate ‘diet/energy balance’ effects independent from ‘body weight’ effects on various metabolic and behavioral parameters using the Diet Switch feeding paradigm in mice. [We conducted] unbiased gene expression analysis of the nutrient-sensing circumventricular hypothalamus [using RNA-seq]. Remarkably, only two genes responded to diet/energy balance (neuropeptide y [npy] and agouti-related peptide [agrp]), while others were related only to body weight. Furthermore, linear regression models revealed that npy and agrp showed similar modifiability by diet/energy balance and body weight compared to electroencephalographic-measured sleep/wake behavior.

2018-05-17 | GSE104709 | GEO

Maternal Undernutrition Results in Transcript Changes in Male Offspring that May Promote Resistance to High Fat Diet Induced Weight Gain

Project description:Maternal nutrition during embryonic development and lactation influences multiple aspects of offspring health. Using mice, this study investigates the effects of maternal caloric restriction (CR) during mid-gestation and lactation on offspring neonatal development and on adult metabolic function when challenged by a high fat diet (HFD). The CR maternal model produced male and female offspring that were significantly smaller, in terms of weight and length, and females had delayed puberty. Adult offspring born to CR dams had a sexually dimorphic response to the high fat diet. Compared to offspring of maternal control dams, adult female, but not male, CR offspring gained more weight in response to high fat diet at 10 weeks. In adipose tissue of male HFD offspring, maternal undernutrition resulted in blunted expression of genes associated with weight gain and increased expression of genes that protect against weight gain. Regardless of maternal nutrition status, HFD male offspring showed increased expression of genes associated with nonalcoholic liver disease (NAFLD). Furthermore, we observed significant, sexually dimorphic differences in serum TSH. These data reveal tissue- and sex-specific changes in gene and hormone regulation following mild maternal undernutrition, which may offer protection against diet induced weight gain in adult male offspring.

2024-01-04 | GSE247985 | GEO

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Project description:Remembrances of traumata range among the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that in mice successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes as revealed by whole genome RNA sequencing, which is accompanied by higher metabolic, synaptic and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata. 3 biological replicates per group were analyzed. The material analyzed was whole hippocampi from one brain hemisphere, from which total RNA was extracted.

2014-01-04 | E-GEOD-53794 | biostudies-arrayexpress

A nutritional memory impairs transcriptional, metabolic and survival response to dietary restriction in old mice

Project description:Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at ¬old age remains elusive. Here, we conducted a late-life DR switch experiment employing 800 mice, by switching old animals from ad libitum (AL) to DR and vice versa. Strikingly, the switch from DR-to-AL acutely increased mortality, while the switch from AL-to-DR caused only a weak and gradual increase in survival, highlighting a memory of earlier nutrition. A significant association between fat preservation and survival response pointed to the adipose tissue as a potential memory source. Consistently, post-switch RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrated that the transcriptional and metabolic program of chronic DR remained largely refractory to the AL-to-DR switch in the two fat tissues, particularly in WAT. This loss of transcriptional flexibility coincides with a major proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Integration of lipidomics confirmed impaired membrane lipogenesis and limited mitochondrial copy number increase under late-life DR as functional consequences of this memory effect. Together, our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.

2019-08-28 | GSE124772 | GEO

SAPS3 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge

Project description:Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanism underneath that is not clear. Here, we demonstrate serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is a negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Either whole-body or liver-specific deletion of SAPS3 protects male mice against the HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout male mice under HFD. Together, our results reveal that SAPS3 is a negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes.

2023-01-26 | PXD039625 | Pride

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