Sex-specific changes in energy demand during the preplaque stage in a transgenic Alzheimer’s mouse model Rongwan Sun, Leonie-Kim Zimbalski, Stefanie Schreyer, David Baidoe-Ansah, Aida Harutyunyan, et al. Biology of Sex Differences, 2025 Background Cognitive deficits and brain glucose hypometabolism, lipid peroxidation and mitochondrial dysfunction are early pathological events in murine models and patients with Alzheimer’s disease (AD). Data from our previous research indicate that transgenic mice of the APP23 line, a murine AD model, exhibited higher energy expenditure and mitochondrial dysregulation in the liver as early as 3 months of age, which is considered the preplaque stage. Since women have a higher risk and mortality rate for AD, with potential sex-specific confounders as longevity, biological, genetic, and social factors also needing to be considered, sex differences in energy metabolism in AD remain insufficiently investigated. Methods Here, we investigated sex-specific differences in mitochondrial respiration and metabolic profiles of 3–4-month-old, preplaque APP23 transgenic mice, in which we did not detect inflammatory signals and pathological amyloid-beta (Aß) plaques in brain or liver. Their mitochondrial respiration was assessed measuring oxygen consumption rates in isolated primary hepatocytes, stromal vascular cells (SVCs) and re-differentiated adipocytes. Furthermore, we analyzed energy balance, including food intake, locomotor activity, energy expenditure and fecal calorie loss. Results We observed an upregulation of hepatic mitochondrial respiration in preplaque APP23 females. Female-derived SVCs and differentiated adipocytes improved mitochondrial flexibility with palmitate loading in vitro, which was in line with decreased plasma triglycerides in preplaque APP23 females in vivo. However, no differences in mitochondrial respiration were detected in hepatocytes and re-differentiated adipocytes derived from male APP23 mice. Furthermore, we corroborated an increased mortality during the preplaque stage, particularly in females, which exhibited reduced hyperactivity and caloric intake before death compared to survivors. Conclusions Our data demonstrate that preplaque APP23 female mice have disequilibrated mitochondrial oxidation in hepatocytes and adipocytes as well as higher energy expenditure due to increased activity before AD manifestation. In contrast, male APP23 mice did not exhibit such metabolic changes. Constant excessive energy loss and limited calorie supply potentially contribute to the higher risk of mortality, especially in APP23 females during young adulthood. Plain english summary Alzheimer’s disease (AD) affects men and women differently, with women at higher risk and mortality. This study explored sex differences in energy metabolism using APP23 transgenic mice, a model of AD, at young age (3–4 months) - before pathological amyloid-beta (Aß) plaques develop in the brain and liver. Female APP23 mice showed increased mitochondrial activity in liver and fat cells, higher energy expenditure, and more movement while eating less. They also excreted more energy in their feces. Notably, female APP23 mice had a lower survival rate than males. Before death, they became less active and ate even less, suggesting an inability to maintain energy balance. These findings indicate that female APP23 mice experience excessive energy loss, which may contribute to early mortality. Understanding these sex-specific metabolic differences could provide new insights into AD progression and highlight the need for targeted treatments.
Soft Drink Consumption and Depression Mediated by Gut Microbiome Alterations Sharmili Edwin Thanarajah, Adèle H. Ribeiro, Jaehyun Lee, Nils R. Winter, Frederike Stein, et al. JAMA Psychiatry, 2025 Importance Soft drink consumption is linked to negative physical and mental health outcomes, but its association with major depressive disorder (MDD) and the underlying mechanisms remains unclear. Objective To examine the association between soft drink consumption and MDD diagnosis and severity and whether this association is mediated by changes in the gut microbiota, particularly Eggerthella and Hungatella abundance. Design, Setting, and Participants This multicenter cohort study was conducted in Germany using cross-sectional data from the Marburg-Münster Affective Cohort. Patients with MDD and healthy controls (aged 18-65 years) recruited from the general population and primary care between September 2014 and September 2018 were analyzed. Data analyses were conducted between May and December 2024. Main Outcomes and Measures Primary analyses included multivariable regression and analysis of variance (ANOVA) models examining the association between soft drink consumption and MDD diagnosis and symptom severity, controlling for site and education, and Eggerthella and Hungatella abundance, controlling for site, education, and library size. Mediation analyses tested whether microbiota abundance mediated the soft drink–MDD link. Results A total of 405 patients with MDD (275 female patients [67.9%]; mean [SD] age, 36.37 [13.33] years) and 527 healthy controls (345 female controls [65.5%]; mean [SD] age, 35.33 [13.13] years) were included. Soft drink consumption predicted MDD diagnosis (odds ratio [OR], 1.081; 95% CI, 1.008-1.159; P = .03) and symptom severity ( P < .001; partial η 2 [ηp 2 ], 0.012; 95% CI, 0.004-0.035), with stronger effects in women (diagnosis: OR, 1.167; 95% CI, 1.054-1.292; P = .003; severity: P < .001; ηp 2 , 0.036; 95% CI, 0.011-0.062). In women, consumption was linked to increased Eggerthella ( P = .007; ηp 2 , 0.017; 95% CI, 0.0002-0.068), but not Hungatella abundance. Mediation analyses confirmed that Eggerthella significantly mediated the soft drink–MDD association (diagnosis: P = .011; severity: P = .005), explaining 3.82% and 5.00% of the effect, respectively. Conclusions and Relevance In this cohort study, it was found that soft drink consumption may contribute to MDD through gut microbiota alterations, notably involving Eggerthella . Public health strategies to reduce soft drink intake may help mitigate depression risk, especially among vulnerable populations; in addition, interventions for depression targeting the microbiome composition appear promising.
Acute elevated dietary fat alone is not sufficient to decrease AgRP projections in the paraventricular nucleus of the hypothalamus in mice Selma Yagoub, Robert A. Chesters, Jonathan Ott, Jiajie Zhu, Lídia Cantacorps, et al. Scientific Reports, 2024 Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes.
Fasting-induced activity changes in MC3R neurons of the paraventricular nucleus of the thalamus Robert A Chesters, Jiajie Zhu, Bethany M Coull, David Baidoe-Ansah, Lea Baumer, et al. Life Science Alliance, 2024 The brain controls energy homeostasis by regulating food intake through signaling within the melanocortin system. Whilst we understand the role of the hypothalamus within this system, how extra-hypothalamic brain regions are involved in controlling energy balance remains unclear. Here we show that the melanocortin 3 receptor (MC3R) is expressed in the paraventricular nucleus of the thalamus (PVT). We tested whether fasting would change the activity of MC3R neurons in this region by assessing the levels of c-Fos and pCREB as neuronal activity markers. We determined that overnight fasting causes a significant reduction in pCREB levels within PVT-MC3R neurons. We then questioned whether perturbation of MC3R signaling, during fasting, would result in altered refeeding. Using chemogenetic approaches, we show that modulation of MC3R activity, during the fasting period, does not impact body weight regain or total food intake in the refeeding period. However, we did observe significant differences in the pattern of feeding-related behavior. These findings suggest that the PVT is a region where MC3R neurons respond to energy deprivation and modulate refeeding behavior.
Gut-derived peptide hormone receptor expression in the developing mouse hypothalamus Lídia Cantacorps, Bethany M. Coull, Joanne Falck, Katrin Ritter, Rachel N. Lippert Plos One, 2023 Objective In adult organisms, a number of receptors have been identified which modulate metabolic processes related to peptides derived from the intestinal tract. These receptors play significant roles in glucose homeostasis, food intake and energy balance. Here we assess these classical metabolic receptors and their expression as well as their potential role in early development of hypothalamic neuronal circuits. Methods Chow-fed C57BL6/N female mice were mated and hypothalamic tissue was collected from offspring across postnatal development (postnatal day 7–21). Subsequent qPCR and Western Blot analyses were used to determine mRNA and protein changes in gut-derived peptide hormone receptors. Correlations to body weight, blood glucose and circulating leptin levels were analyzed. Results We describe the gene expression and dynamic protein regulation of key gut-derived peptide hormone receptors in the early postnatal period of the mouse brain. Specifically, we show changes to Gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide 1 receptor (GLP1R), and cholecystokinin receptor 2 (CCK2R) in the developing hypothalamus. The changes to GIPR and InsR seem to be strongly negatively correlated with body weight. Conclusions This comprehensive analysis underscores the need to understand the roles of maternal-derived circulating gut hormones and their direct effect on offspring brain development.
Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior Carla Igual Gil, Bethany M Coull, Wenke Jonas, Rachel N Lippert, Susanne Klaus, et al. Life Science Alliance, 2022 Growth differentiation factor 15 (GDF15) is a mitochondrial stress-induced cytokine that modulates energy balance in an endocrine manner. However, the importance of its brainstem-restricted receptor GDNF family receptor alpha-like (GFRAL) to mediate endocrine GDF15 signaling to the brain upon mitochondrial dysfunction is still unknown. Using a mouse model with muscle-specific mitochondrial dysfunction, we here show that GFRAL is required for activation of systemic energy metabolism via daytime-restricted anorexia but not responsible for muscle wasting. We further find that muscle mitochondrial stress response involves a GFRAL-dependent induction of hypothalamic corticotropin-releasing hormone, without elevated corticosterone levels. Finally, we identify that GFRAL signaling governs an anxiety-like behavior in male mice with muscle mitochondrial dysfunction, with females showing a less robust GFRAL-dependent anxiety-like phenotype. Together, we here provide novel evidence of a mitochondrial stress-induced muscle–brain crosstalk via the GDF15-GFRAL axis to modulate food intake and anxiogenic behavior.
Midbrain Tet1 dosage defines inter-individual binge-eating susceptibility T Gruber, RA Chesters, L Fagnocchi, X Yu, Z Fu, K Gallik, H Backes, ... bioRxiv, 2026.03. 14.711800 , 2026 2026
Soft Drink Consumption and Depression Mediated by Gut Microbiome Alterations S Edwin Thanarajah, AH Ribeiro, J Lee, NR Winter, F Stein, RN Lippert, ... JAMA psychiatry 82 (11), 1095-1102 , 2025 2025 Citations: 7
Maternal stressors disrupt mouse placental proteome and fetal brain development in a sex-specific fashion through inflammation and oxidative stress C Musillo, MA Ajmone-Cat, R De Simone, R Tassinari, F Maranghi, S Tait, ... Molecular Psychiatry 30 (11), 5072-5083 , 2025 2025 Citations: 12
Protective effects of prenatal Omega-3 supplementation on brain and behavioral changes in mouse offspring exposed to a maternal high-fat diet C Musillo, M Samà, RN Lippert, F Cirulli Neuroscience 580, 22 , 2025 2025
Sex-specific changes in energy demand during the preplaque stage in a transgenic Alzheimer’s mouse model R Sun, LK Zimbalski, S Schreyer, D Baidoe-Ansah, A Harutyunyan, ... Biology of sex Differences 16 (1), 54 , 2025 2025 Citations: 1
1238-P: α-MSH as a Predictor of Maternal Metabolic Health and Fetal Heart Function L Semeia, T Tsengenbayar, J Sbierski-Kind, K Ritter, S Yagoub, ... Diabetes 74 (Supplement_1), 1238-P , 2025 2025
α-MSH positively influences fetal heart rate variability in relation to maternal metabolic state L Semeia, T Tsengenbayar, K Sippel, J Frohlic, AL Birkenfeld, A Fritsche, ... Diabetologie und Stoffwechsel 20 (S 01), P13. 01 , 2025 2025
Microglia mediate the early-life programming of adult glucose control M Valdearcos, ER McGrath, SMB Mayfield, MG Jacuinde, A Folick, ... Cell reports 44 (3) , 2025 2025 Citations: 14
DEP-1 is a brain insulin receptor phosphatase that prevents the simultaneous activation of counteracting metabolic pathways S Chopra, OLJ Kadiri, J Ulke, R Hauffe, W Jonas, S Cheshmeh, L Schmidt, ... Cell reports 43 (12) , 2024 2024 Citations: 2
Maternal stressors disrupt mouse placental proteome and fetal brain development in a sex-specific fashion through inflammation and oxidative stress A Berry, C Musillo, MA Ajmone-Cat, R De Simone, R Tassinari, ... 2024
Fasting-induced activity changes in MC3R neurons of the paraventricular nucleus of the thalamus RA Chesters, J Zhu, BM Coull, D Baidoe-Ansah, L Baumer, L Palm, ... Life Science Alliance 7 (10) , 2024 2024 Citations: 2
Acute elevated dietary fat alone is not sufficient to decrease AgRP projections in the paraventricular nucleus of the hypothalamus in mice S Yagoub, RA Chesters, J Ott, J Zhu, L Cantacorps, K Ritter, RN Lippert Scientific Reports 14 (1), 20043 , 2024 2024
Elevated dietary fat alone is not sufficient to decrease AgRP projections in the paraventricular nucleus of the hypothalamus in mice S Yagoub, R Chesters, J Ott, J Zhu, L Cantacorps, K Ritter, R Lippert 2024
Du sollst nicht essen: warum Menschen auf Nahrung verzichten–interdisziplinäre Zugänge U Kollodzeiski, JE Hafner, RN Lippert, T Bartelmeß, FJ Schweigert, ... 2024
Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice L Cantacorps, J Zhu, S Yagoub, BM Coull, J Falck, RA Chesters, K Ritter, ... Molecular Metabolism 79, 101860 , 2024 2024 Citations: 8
Das Gehirn. Wie ein Organ unsere Essensentscheidungsteuert Die physiologische Kontrolle des Essverhaltens verstehen RN Lippert Du sollst nicht essen, 15-32 , 2023 2023
Gut-derived peptide hormone receptor expression in the developing mouse hypothalamus L Cantacorps, BM Coull, J Falck, K Ritter, RN Lippert PLoS One 18 (8), e0290043 , 2023 2023 Citations: 4
Thalamic melanocortin system regulation: development, energy state and genetic influences S Yagoub, J Zhu, L Cantacorps, K Ritter, R Lippert Neuroscience Applied 2, 101039 , 2023 2023
Maternal diabetes and metformin exposure affect offspring brain development in a sex-dependent manner LC Centellas, J Zhu, S Yagoub, R Lippert Neuroscience Applied 2, 101036 , 2023 2023
Modulation of melanocortin-3-receptor neurons affects food intake under stress exposure J Zhu, R Lippert, L Cantacorps, S Yagoub, K Ritter Neuroscience Applied 2, 101068 , 2023 2023
MOST CITED SCHOLAR PUBLICATIONS
Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice LB Buckman, MM Thompson, RN Lippert, TS Blackwell, FE Yull, ... Molecular metabolism 4 (1), 58-63 , 2015 2015 Citations: 172
MC3R links nutritional state to childhood growth and the timing of puberty BYH Lam, A Williamson, S Finer, FR Day, JA Tadross, ... Nature 599 (7885), 436-441 , 2021 2021 Citations: 165
Food intake recruits orosensory and post-ingestive dopaminergic circuits to affect eating desire in humans SE Thanarajah, H Backes, AG DiFeliceantonio, K Albus, AL Cremer, ... Cell metabolism 29 (3), 695-706. e4 , 2019 2019 Citations: 134
Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution W Leung, CD Shaffer, LK Reed, ST Smith, W Barshop, W Dirkes, ... G3: Genes, Genomes, Genetics 5 (5), 719-740 , 2015 2015 Citations: 118
Gender-specific roles for the melanocortin-3 receptor in the regulation of the mesolimbic dopamine system in mice RN Lippert, KLJ Ellacott, RD Cone Endocrinology 155 (5), 1718-1727 , 2014 2014 Citations: 105
Physiological roles of the melanocortin MC3 receptor BJ Renquist, RN Lippert, JA Sebag, KLJ Ellacott, RD Cone European journal of pharmacology 660 (1), 13-20 , 2011 2011 Citations: 83
Regulation of energy rheostasis by the melanocortin-3 receptor M Ghamari-Langroudi, I Cakir, RN Lippert, P Sweeney, MJ Litt, ... Science advances 4 (8), eaat0866 , 2018 2018 Citations: 81
Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice RN Lippert, S Hess, P Klemm, LM Burgeno, T Jahans-Price, ME Walton, ... The Journal of Clinical Investigation 130 (7), 3761-3776 , 2020 2020 Citations: 74
Time-dependent assessment of stimulus-evoked regional dopamine release RN Lippert, AL Cremer, S Edwin Thanarajah, C Korn, T Jahans-Price, ... Nature Communications 10 (1), 336 , 2019 2019 Citations: 48
Maternal metabolic programming of the developing central nervous system: unified pathways to metabolic and psychiatric disorders RN Lippert, JC Brüning Biological Psychiatry 91 (10), 898-906 , 2022 2022 Citations: 46
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Organization of neural systems expressing melanocortin‐3 receptors in the mouse brain: Evidence for sexual dimorphism MN Bedenbaugh, SC Brener, J Maldonado, RN Lippert, P Sweeney, ... Journal of Comparative Neurology 530 (16), 2835-2851 , 2022 2022 Citations: 26
Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior C Igual Gil, BM Coull, W Jonas, RN Lippert, S Klaus, M Ost Life Science Alliance 5 (11), e202201495 , 2022 2022 Citations: 18
Microglia mediate the early-life programming of adult glucose control M Valdearcos, ER McGrath, SMB Mayfield, MG Jacuinde, A Folick, ... Cell reports 44 (3) , 2025 2025 Citations: 14
Maternal stressors disrupt mouse placental proteome and fetal brain development in a sex-specific fashion through inflammation and oxidative stress C Musillo, MA Ajmone-Cat, R De Simone, R Tassinari, F Maranghi, S Tait, ... Molecular Psychiatry 30 (11), 5072-5083 , 2025 2025 Citations: 12
Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice L Cantacorps, J Zhu, S Yagoub, BM Coull, J Falck, RA Chesters, K Ritter, ... Molecular Metabolism 79, 101860 , 2024 2024 Citations: 8
Genes BYH Lam, A Williamson, S Finer, FR Day, JA Tadross, ... Health Research T, Trembath RC, Martin HC, Coll AP, Rowitch DH, Wareham NJ … , 2021 2021 Citations: 8
Soft Drink Consumption and Depression Mediated by Gut Microbiome Alterations S Edwin Thanarajah, AH Ribeiro, J Lee, NR Winter, F Stein, RN Lippert, ... JAMA psychiatry 82 (11), 1095-1102 , 2025 2025 Citations: 7
Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia CI Gil, BM Coull, W Jonas, R Lippert, M Ost, S Klaus bioRxiv, 2021.09. 22.461199 , 2021 2021 Citations: 6
Gut-derived peptide hormone receptor expression in the developing mouse hypothalamus L Cantacorps, BM Coull, J Falck, K Ritter, RN Lippert PLoS One 18 (8), e0290043 , 2023 2023 Citations: 4