Protective effects of Gαi3 deficiency in a murine heart-failure model of ß1-adrenoceptor overexpression.

We have shown that in murine cardiomyopathy caused by overexpression of the ß1-adrenoceptor, Gαi2-deficiency is detrimental. Given the growing evidence for isoform-specific Gαi-functions, we now examined the consequences of Gαi3 deficiency in the same heart-failure model. Mice overexpressing cardiac ß1-adrenoceptors with (ß1-tg) or without Gαi3-expression (ß1-tg/Gαi3-/-) were compared to C57BL/6 wildtypes and global Gαi3-knockouts (Gαi3-/-). The life span of ß1-tg mice was significantly shortened but improved when Gαi3 was lacking (95% CI: 592-655 vs. 644-747 days). At 300 days of age, left-ventricular function and survival rate were similar in all groups. At 550 days of age, ß1-tg but not ß1-tg/Gαi3-/- mice displayed impaired ejection fraction (35 ± 18% vs. 52 ± 16%) compared to wildtype (59 ± 4%) and Gαi3-/- mice (60 ± 5%). Diastolic dysfunction of ß1-tg mice was prevented by Gαi3 deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in ß1-tg hearts was significantly attenuated in ß1-tg/Gαi3-/- mice. Transcript levels of phospholamban, ryanodine receptor 2, and cardiac troponin I were similar in all groups. However, Western blots and phospho-proteomic analyses showed that in ß1-tg, but not ß1-tg/Gαi3-/- ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac ß1-adrenoceptor, Gαi3 deficiency slows or even prevents cardiomyopathy and increases shortened life span. Previously, we found Gαi2 deficiency to aggravate cardiac dysfunction and mortality in the same heart-failure model. Our findings indicate isoform-specific interventions into Gi-dependent signaling to be promising cardio-protective strategies.

Implementing nutritional medicine into medical curricula: A student-initiated course improves knowledge and attitudes.

BACKGROUND & AIMS: Although the risks and opportunities of nutrition in health trajectories are well known, it is rarely addressed in doctors' daily routine. This is partly related to physicians' lack of confidence in their ability to provide nutritional counselling, possibly due to insufficient training in medical school. Our study aimed at assessing the status quo of nutrition in the German medical curricula and the impact of a recently implemented, student-initiated online teaching initiative on perceived competence, knowledge and attitudes. METHODS: "Eat This!" was the first Germany-wide initiative for online nutritional medicine (NM) education, consisting of 11 digital lectures on nutrition basics, nutrition medicine and public health nutrition. The contact time with NM during studies as well as the effects on students' attitudes towards NM, their self-perceived competence in NM and their nutrition knowledge were assessed from October 2020 to February 2021 in a cross-sectional as well as a prospective study using online questionnaires. RESULTS: Over 1500 medical students from 42 German faculties participated in the lecture series and the online survey. One hundred and twenty-two students formed a control group. Although considering the topic relevant, students rated their training in NM as insufficient, in terms of both quality and quantity. Initially, they did not feel able to counsel patients and rated their knowledge as low. However, self-ratings and the score in a 33-item multiple-choice test knowledge improved by participating in Eat This! as did their attitude towards nutrition and planetary health. No such changes were observed in the control group of 122 students not attending the course. CONCLUSION: Our results show that education in NM at German medical schools is perceived insufficient despite high student interest. But even low-threshold educational options like "Eat This!" can improve students' perceived competence, knowledge, and attitudes, and thus be an efficient and cost-effective way to address related deficits.

A comparison of urinary bladder weight in male and female mice across five models of diabetes and obesity.

Introduction: Diabetes often leads to lower urinary tract dysfunction. The most frequently assessed parameter of urinary bladder dysfunction in animal models of diabetes is an enlargement of the bladder, which is consistently observed in type 1 and less consistently in type 2 diabetes. The vast majority of studies on bladder weight in animal models of diabetes and obesity has been performed in males, and no studies have directly compared this outcome parameter between sexes. Methods: Therefore, we have compared bladder weight and bladder/body weight ratio in five mouse models of obesity and diabetes (RIP-LCMV, db/db, ob/ob (two studies), insulin receptor substrate 2 (IRS2) knock-out mice and mice on a high-fat diet; pre-specified secondary analysis of a previously reported study). Results: In a pooled analysis of the control groups of all studies, females exhibited slightly lower glucose levels, lower body weight, and lower bladder weight, but bladder/body weight ratio was similar in both sexes (0.957 vs. 0.986 mg/g, mean difference 0.029 [-0.06; 0.118]). Among the six diabetic/obese groups, bladder/body weight ratio was similar in both sexes in three but smaller in female mice in three other groups. The mRNA expression of a panel of genes implied in the pathophysiology of bladder enlargement and/or fibrosis and inflammation did not differ systematically between sexes. Conclusions: We conclude that sex differences in diabetes/obesity-associated bladder enlargement may be model dependent.

Improvement of Dietary Habits among German Medical Students by Attending a Nationwide Online Lecture Series on Nutrition and Planetary Health ("Eat This!").

Nutrition is a major influential factor in optimizing human health and environmental sustainability. Medical students often do not follow national dietary guideline recommendations. Raising awareness of a healthy lifestyle is important as physicians with healthy lifestyle behaviors are more likely to counsel on nutrition. Our study aims to evaluate a Germany-wide online lecture series on nutritional medicine, "Eat This!". Before and after the course, 520 medical students who participated and 64 who did not participate in the course (comparison group) filled out an online survey. To assess the students' dietary habits, a validated FFQ was used. According to this questionnaire, only 31% of the lecture participants consumed enough fruits and 24% consumed enough vegetables, while almost half of the students exceeded the recommended maximum amount of crisps and sweets. After attending the lecture series, guideline adherence with respect to fruits and vegetables showed a significant increase, as did awareness of healthy nutrition and percentage of students with low-risk lifestyle habits. Our results show that low-threshold approaches, such as "Eat This!", can positively influence the dietary behaviors and lifestyle habits of medical students. This can help future doctors fulfill their role in the fight against the global burden of non-communicable diseases.

A simple approach of applying blended learning to problem-based learning is feasible, accepted and does not affect evaluation and exam results-a just pre-pandemic randomised controlled mixed-method study.

We tested for feasibility, acceptance, and "non-inferiority" of small-group teaching applying blended learning (i.e., the integration of face-to-face and online instruction) to problem-based learning (bPbL) compared to conventional PbL (cPbL). In a just pre-pandemic, randomised controlled trial, 317 students attended either bPbL or cPbL groups. The first meeting of the bPbL groups took place online via written internet chat, while cPbL groups met on site. All groups met on site the second time. All students had the opportunity to attend lectures either on site or as videos on demand. We analysed student evaluation data, results in a final summative exam, attendance of lectures on site and use of lecture videos. Furthermore, we performed a qualitative analysis of student statements made in semi-structured group interviews about pros and cons of the bPbL approach. There was no difference between students of either bPbL or cPbL groups with respect to exam results (score: 14.3 ± 2.8 vs. 13.8 ± 2.7) or course evaluation. However, relatively more bPbL than cPbL students reported having used lecture videos, while the proportion of those attending lectures on-site was higher among cPbL students. Interviews revealed that some of the bPbL students' experiences were unexpected and feared disadvantages seemed to be less severe than expected. Participation in a blended PbL format did not worsen course evaluations or exam results, but seemed to influence lecture attendance. The combination of face-to-face and digital elements could be suitable as a hybrid approach to digital instruction in the post-pandemic era.

Analysis of 16 studies in nine rodent models does not support the hypothesis that diabetic polyuria is a main reason of urinary bladder enlargement.

The urinary bladder is markedly enlarged in the type 1 diabetes mellitus model of streptozotocin-injected rats, which may contribute to the frequent diabetic uropathy. Much less data exists for models of type 2 diabetes. Diabetic polyuria has been proposed as the pathophysiological mechanism behind bladder enlargement. Therefore, we explored such a relationship across nine distinct rodent models of diabetes including seven models of type 2 diabetes/obesity by collecting data on bladder weight and blood glucose from 16 studies with 2-8 arms each; some studies included arms with various diets and/or pharmacological treatments. Data were analysed for bladder enlargement and for correlations between bladder weight on the one and glucose levels on the other hand. Our data confirm major bladder enlargement in streptozotocin rats and minor if any enlargement in fructose-fed rats, db/db mice and mice on a high-fat diet; enlargement was present in some of five not reported previously models. Bladder weight was correlated with blood glucose as a proxy for diabetic polyuria within some but not other models, but correlations were moderate to weak except for RIP-LCMV mice (r 2 of pooled data from all studies 0.0621). Insulin levels also failed to correlate to a meaningful extent. Various diets and medications (elafibranor, empagliflozin, linagliptin, semaglutide) had heterogeneous effects on bladder weight that often did not match their effects on glucose levels. We conclude that the presence and extent of bladder enlargement vary markedly across diabetes models, particularly type 2 diabetes models; our data do not support the idea that bladder enlargement is primarily driven by glucose levels/glucosuria.

Inhibitory effects on L- and N-type calcium channels by a novel CaVß1 variant identified in a patient with autism spectrum disorder.

Voltage-gated calcium channel (VGCC) subunits have been genetically associated with autism spectrum disorders (ASD). The properties of the pore-forming VGCC subunit are modulated by auxiliary ß-subunits, which exist in four isoforms (CaVß1-4). Our previous findings suggested that activation of L-type VGCCs is a common feature of CaVß2 subunit mutations found in ASD patients. In the current study, we functionally characterized a novel CaVß1b variant (p.R296C) identified in an ASD patient. We used whole-cell and single-channel patch clamp to study the effect of CaVß1b_R296C on the function of L- and N-type VGCCs. Furthermore, we used co-immunoprecipitation followed by Western blot to evaluate the interaction of the CaVß1b-subunits with the RGK-protein Gem. Our data obtained at both, whole-cell and single-channel levels, show that compared to a wild-type CaVß1b, the CaVß1b_R296C variant inhibits L- and N-type VGCCs. Interaction with and modulation by the RGK-protein Gem seems to be intact. Our findings indicate functional effects of the CaVß1b_R296C variant differing from that attributed to CaVß2 variants found in ASD patients. Further studies have to detail the effects on different VGCC subtypes and on VGCC expression.

A simulation-based module in pharmacology education reveals and addresses medical students' deficits in leading prescription talks.

Although doctor-patient communication is essential for drug prescription, the literature reveals deficits in this area. An educational approach at the Cologne medical faculty aims at identifying and addressing those deficits in medical students.Fifth-year medical students first conducted a simulated prescription talk spontaneously. Subsequently, the conversation was discussed with peer students. A pharmacist moderated the discussion based upon a previously developed conversation guide. Afterwards, the same student had the conversation again, but as if for the first time. Conversations were video-recorded, transcribed and subjected to quantitative content analysis. Four days after the simulation, the students who conducted the talk, those who observed and discussed it, and students who did neither, completed a written test that focused on the content of an effective prescription talk.Content analysis revealed clear deficits in spontaneously led prescription talks. Even essential information as on adverse drug reactions were often lacking. Prescription talks became clearly more informative and comprehensive after the short, guided peer discussion. With regard to a comprehensive, informative prescription talk, the written test showed that both the students who conducted the talk and those who only observed it performed clearly better than the students who did not participate in the educational approach.Deficits regarding prescription talks are present in 5th year medical students. We provide an approach to both identify and address these deficits. It thus may be an example for training medical students in simulated and clinical environments like the EACPT recommended to improve pharmacology education.

Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation.

Depolarization drives neuronal plasticity. However, whether depolarization drives sensitization of peripheral nociceptive neurons remains elusive. By high-content screening (HCS) microscopy, we revealed that depolarization of cultured sensory neurons rapidly activates protein kinase A type II (PKA-II) in nociceptors by calcium influx through CaV1.2 channels. This effect was modulated by calpains but insensitive to inhibitors of cAMP formation, including opioids. In turn, PKA-II phosphorylated Ser1928 in the distal C terminus of CaV1.2, thereby increasing channel gating, whereas dephosphorylation of Ser1928 involved the phosphatase calcineurin. Patch-clamp and behavioral experiments confirmed that depolarization leads to calcium- and PKA-dependent sensitization of calcium currents ex vivo and local peripheral hyperalgesia in the skin in vivo. Our data suggest a local activity-driven feed-forward mechanism that selectively translates strong depolarization into further activity and thereby facilitates hypersensitivity of nociceptor terminals by a mechanism inaccessible to opioids.

Aspects of Medication and Patient participation-an Easy guideLine (AMPEL). A conversation guide increases patients' and physicians' satisfaction with prescription talks.

Patients want more information and active participation in medical decisions. Information and active participation correlate with increased adherence. A conversation guide, combining patient-relevant drug information with steps of shared decision-making, was developed to support physicians in effective and efficient prescription talks. Six GP trainees in community-based primary care practices participated in a controlled pilot study in sequential pre-post design. Initially, they conducted 41 prescription talks as usual, i.e., without knowing the guide. Then, they conducted 23 talks considering the guide (post-intervention phase). Immediately after the respective talk, patients filled in a questionnaire on satisfaction with the information on medication and physician-patient interaction, and physicians about their satisfaction with the talk and the application of the guide. Patients felt better informed after guide-based prescription talks (e.g., SIMS-D in median 10 vs. 17, p < 0.05), more actively involved (KPF-A for patient activation 2.9 ± 0.8 vs. 3.6 ± 0.8, p < 0.05), and more satisfied with the physician-patient interaction. Physicians rated the guide helpful and feasible. Their satisfaction with the conversation was significantly enhanced during the post-intervention phase. The evaluation of the duration of the talk was not influenced. Enhanced patients' and physicians' satisfaction with prescription talks encourages further examinations of the conversation guide. We invite physicians to try our guide in everyday medical practice.

Inhibition of EIF-5A prevents apoptosis in human cardiomyocytes after malaria infection.

In this study, a determination of Troponin I and creatine kinase activity in whole-blood samples in a cohort of 100 small infants in the age of 2-5 years from Uganda with complicated Plasmodium falciparum malaria suggests the prevalence of cardiac symptoms in comparison to non-infected, healthy patients. Troponin I and creatine kinase activity increased during infection. Different reports showed that complicated malaria coincides with hypoxia in children. The obtained clinical data prompted us to further elucidate the underlying regulatory mechanisms of cardiac involvement in human cardiac ventricular myocytes. Complicated malaria is the most common clinical presentation and might induce cardiac impairment by hypoxia. Eukaryotic initiation factor 5A (eIF-5A) is involved in hypoxia induced factor (HIF-1α) expression. EIF-5A is a protein posttranslationally modified by hypusination involving catalysis of the two enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase. Treatment of human cardiomyocytes with GC7, an inhibitor of DHS, catalyzing the first step in hypusine biosynthesis led to a decrease in proinflammatory and proapoptotic myocardial caspase-1 activity in comparison to untreated cardiomyocytes. This effect was even more pronounced after co-administration of GC7 and GPI from P. falciparum simulating the pathology of severe malaria. Moreover, in comparison to untreated and GC7-treated cardiomyocytes, co-administration of GC7 and GPI significantly decreased the release of cytochrome C and lactate from damaged mitochondria. In sum, coadministration of GC7 prevented cardiac damage driven by hypoxia in vitro. Our approach demonstrates the potential of the pharmacological inhibitor GC7 to ameliorate apoptosis in cardiomyocytes in an in vitro model simulating severe malaria. This regulatory mechanism is based on blocking EIF-5A hypusination.

Autism-associated mutations in the CaVß2 calcium-channel subunit increase Ba2+-currents and lead to differential modulation by the RGK-protein Gem.

Voltage-gated calcium-channels (VGCCs) are heteromers consisting of several subunits. Mutations in the genes coding for VGCC subunits have been reported to be associated with autism spectrum disorder (ASD). In a previous study, we identified electrophysiologically relevant missense mutations of CaVß2 subunits of VGCCs. From this, we derived the hypothesis that several CaVß2-mutations associated with ASD show common features sensitizing LTCCs and/or enhancing currents. Using a CaVß2d backbone, we performed extensive whole-cell and single-channel patch-clamp analyses of Ba2+ currents carried by Cav1.2 pore subunits co-transfected with the previously described CaVß2 mutations (G167S, S197F) as well as a recently identified point mutation (V2D). Furthermore, the interaction of the mutated CaVß2d subunits with the RGK protein Gem was analyzed by co-immunoprecipitation assays and electrophysiological studies. Patch-clamp analyses revealed that all mutations increase Ba2+ currents, e.g. by decreasing inactivation or increasing fraction of active sweeps. All CaVß2 mutations interact with Gem, but differ in the extent and characteristics of modulation by this RGK protein (e.g. decrease of fraction of active sweeps: CaVß2d_G167S > CaVß2d_V2D > CaVß2d_S197F). In conclusion, patch-clamp recordings of ASD-associated CaVß2d mutations revealed differential modulation of Ba2+ currents carried by CaV1.2 suggesting kind of an "electrophysiological fingerprint" each. The increase in current finally observed with all CaVß2d mutations analyzed might contribute to the complex pathophysiology of ASD and by this indicate a possible underlying molecular mechanism.

Direct, gabapentin-insensitive interaction of a soluble form of the calcium channel subunit α2δ-1 with thrombospondin-4.

The α2δ-1 subunit of voltage-gated calcium channels binds to gabapentin and pregabalin, mediating the analgesic action of these drugs against neuropathic pain. Extracellular matrix proteins from the thrombospondin (TSP) family have been identified as ligands of α2δ-1 in the CNS. This interaction was found to be crucial for excitatory synaptogenesis and neuronal sensitisation which in turn can be inhibited by gabapentin, suggesting a potential role in the pathogenesis of neuropathic pain. Here, we provide information on the biochemical properties of the direct TSP/α2δ-1 interaction using an ELISA-style ligand binding assay. Our data reveal that full-length pentameric TSP-4, but neither TSP-5/COMP of the pentamer-forming subgroup B nor TSP-2 of the trimer-forming subgroup A directly interact with a soluble variant of α2δ-1 (α2δ-1S). Interestingly, this interaction is not inhibited by gabapentin on a molecular level and is not detectable on the surface of HEK293-EBNA cells over-expressing α2δ-1 protein. These results provide biochemical evidence that supports a specific role of TSP-4 among the TSPs in mediating the binding to neuronal α2δ-1 and suggest that gabapentin does not directly target TSP/α2δ-1 interaction to alleviate neuropathic pain.

"Hopefully, I will never forget that again" - sensitizing medical students for drug safety by working on cases and simulating doctor-patient communication.

Objective: This project is part of the "PJ-STArT-Block", a one-week course preparing 10th semester medical students for their final practical year. The focus is on sensitizing students to aspects of medication safety by becoming aware of their skills and their deficits in terms of application and communication of pharmacological knowledge. The modules were evaluated regarding feasibility, acceptance and possible effects. Furthermore, the areas in which students see their pharmacological deficits or learning successes were gathered. Methods: In simulated physician-patient conversations, the students are to identify drug-related problems such as medication errors, adverse drug events or interactions. Together with their fellow students and under medical or pharmaceutical moderation, they then have to find solutions for the identified problems and communicate these solutions to the patients. Based on paper cases, students practice, reflect, and discuss the research of reliable information about drugs and medication therapy. The written evaluation included the evaluation by school grades and the possibility of comments in free text. A content analysis of interviews with students at the beginning of the project aimed to identify areas of pharmacology in which they see their own deficits. Results: Evaluation results including the free text comments indicate students' acceptance of our pharmacology modules. According to this, the students realize the importance of aspects relevant for medication safety. The areas mentioned in 35 interviews in which students localize deficits, correspond to the topics that were intended when conceiving the modules and which are important for medication safety (e.g. interactions, adverse drug effects, dosages). Conclusion: Implementation of context-based, application-oriented teaching formats as recently claimed for pharmacological education to improve the quality of prescriptions, is possible, as the Cologne example shows. The student evaluation turns out positively and indicates a critical self-reflection. The students identified various pharmacological deficits in themselves, which have since been confirmed and quantified in another study.

Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin.

Voltage-dependent calcium (CaV) 1.3 channels are involved in the control of cellular excitability and pacemaking in neuronal, cardiac, and sensory cells. Various proteins interact with the alternatively spliced channel C-terminus regulating gating of CaV1.3 channels. Binding of a regulatory calcium-binding protein calmodulin (CaM) to the proximal C-terminus leads to the boosting of channel activity and promotes calcium-dependent inactivation (CDI). The C-terminal modulator domain (CTM) of CaV1.3 channels can interfere with the CaM binding, thereby inhibiting channel activity and CDI. Here, we compared single-channel gating behavior of two natural CaV1.3 splice isoforms: the long CaV1.342 with the full-length CTM and the short CaV1.342A with the C-terminus truncated before the CTM. We found that CaM regulation of CaV1.3 channels is dynamic on a minute timescale. We observed that at equilibrium, single CaV1.342 channels occasionally switched from low to high open probability, which perhaps reflects occasional binding of CaM despite the presence of CTM. Similarly, when the amount of the available CaM in the cell was reduced, the short CaV1.342A isoform showed patterns of the low channel activity. CDI also underwent periodic changes with corresponding kinetics in both isoforms. Our results suggest that the competition between CTM and CaM is influenced by calcium, allowing further fine-tuning of CaV1.3 channel activity for particular cellular needs.

Development of perceived pharmacological deficits of medical students and alumni supports claim for continuous and more application-oriented education.

Medical students' prescribing competencies are insufficient. So far, surveys focused on final-year students. Knowledge and confidence seem important, but their development during medical studies are unclear. This study investigated whether students perceived deficits in pharmacological knowledge change during medical studies. Alumni were included to look for changes occurring after graduation. Medical students at different stages of their studies were invited to fill in paper-and-pencil (6th-, 8th-, 9th- and 10th-term students) or online questionnaires (final-year students and alumni) regarding their self-assessed deficits in pharmacology. Questionnaires have been developed based on previous interviews with 10th-term students. We differentiated between declarative and application-oriented knowledge. In total, data from 816 participants could be analysed. Self-assessment regarding declarative knowledge changed during medical studies, being more sceptical in terms without pharmacology courses. Of note, self-assessment of application-oriented knowledge remained constantly low throughout, although our pharmacology courses use problem-based learning. Tenth-term students were most sceptical, perhaps influenced by an obligatory, formative, simulation-based, 1-week course, preparing students for their final practical year. Compared to students, alumni were significantly less sceptical regarding application-oriented knowledge. Students' self-assessment of deficits in pharmacological knowledge changes throughout their studies, presumably in association with pharmacology courses. Overall, students are rather sceptical, especially with regard to application-oriented knowledge. Our data further substantiate the European Association for Clinical Pharmacology and Therapeutics (EACPT) recommendations to improve pharmacology education throughout the entire medical curriculum, e.g. by providing more training in simulated and clinical environments.

Does teaching social and communicative competences influence dental students' attitudes towards learning communication skills? A comparison between two dental schools in Germany.

Introduction: Teaching social and communicative competences has become an important part of undergraduate dental education. The aim of this study was to explore the influence of a longitudinal curriculum, addressing social and communication skills, on dental students' attitudes towards learning these skills. Material and methods: Data on the attitudes towards learning communication skills were collected at two German universities and compared in a cross-sectional survey. 397 dental students were included, 175 students attended a longitudinal curriculum addressing social and communicative competences while 222 students did not. The dental students' attitude towards learning communication skills was measured by a German version of the Communication Skills Attitude Scale (CSAS-D). Results: Dental students who participated in a longitudinal communication curriculum had significantly lower negative attitudes towards learning communication skills than students who did not attend such courses. Differences in positive attitudes could not be found. Significant interaction effects were found for the factors gender and section of study: female students in the clinical section of their study who participated in the longitudinal curriculum reported higher positive attitudes and lower negative attitudes compared to female students in the preclinical section of study. Conclusion: The results of this study indicate that a longitudinal curriculum addressing communication skills can enhance positive and reduce negative attitudes towards learning communication skills. More longitudinal data is needed to explore to what extent gender affects development of communication skills and how students' attitudes towards learning communication change in the long run.

Renal Metabolic Programming Is Linked to the Dynamic Regulation of a Leptin-Klf15 Axis and Akt/AMPKα Signaling in Male Offspring of Obese Dams.

Childhood obesity is associated with renal diseases. Maternal obesity is a risk factor linked to increased adipocytokines and metabolic disorders in the offspring. Therefore, we studied the impact of maternal obesity on renal-intrinsic insulin and adipocytokine signaling and on renal function and structure. To induce maternal obesity, female mice were fed a high-fat diet (HFD) or a standard diet (SD; control group) prior to mating, during gestation, and throughout lactation. A third group of dams was fed HFD only during lactation (HFD-Lac). After weaning at postnatal day (P)21, offspring of all groups received SD. Clinically, HFD offspring were overweight and insulin resistant at P21. Although no metabolic changes were detected at P70, renal sodium excretion was reduced by 40%, and renal matrix deposition increased in the HFD group. Mechanistically, two stages were differentiated. In the early stage (P21), compared with the control group, HFD showed threefold increased white adipose tissue, impaired glucose tolerance, hyperleptinemia, and hyperinsulinemia. Renal leptin/Stat3-signaling was activated. In contrast, the Akt/ AMPKα cascade and Krüppel-like factor 15 expression were decreased. In the late stage (P70), although no metabolic differences were detected in HFD when compared with the control group, leptin/Stat3-signaling was reduced, and Akt/AMPKα was activated in the kidneys. This effect was linked to an increase of proliferative (cyclinD1/D2) and profibrotic (ctgf/collagen IIIα1) markers, similar to leptin-deficient mice. HFD-Lac mice exhibited metabolic changes at P21 similar to HFD, but no other persistent changes. This study shows a link between maternal obesity and metabolic programming of renal structure and function and intrinsic-renal Stat3/Akt/AMPKα signaling in the offspring.