minocycline and Obesity

Concomitant confluent and reticulated papillomatosis (CRP) and acanthosis nigricans (AN) is rare. We present a case of concomitant CRP and obesity-associated AN in a 12-year-old obese Japanese girl. Curiously, oral minocycline therapy, which has been shown to be effective for CRP, was effective against both CRP and AN. Possible mechanisms by which minocycline could have improved skin lesions of CRP and obesity-associated AN are discussed. In addition, reports of concomitant CRP and obesity-associated AN are reviewed. CRP and obesity-associated AN share common clinicopathological features and some reports have described concomitant CRP and obesity-associated AN. Together with the observation that skin lesions of CRP and obesity-associated AN in the present case responded to oral minocycline therapy, these facts suggest a tight relationship or a common pathogenetic pathway between these pathologies.

Topics: Acanthosis Nigricans; Alkaline Phosphatase; Anti-Bacterial Agents; Biopsy; Blood Glucose; C-Peptide; Child; Female; Humans; Insulin Resistance; Minocycline; Obesity; Papilloma; Rare Diseases; Skin; Skin Neoplasms; Syndrome; Treatment Outcome

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders characterized by deficits in social communication, social interaction, and the presence of restricted repetitive behaviors. The cause of ASD involves complex interactions between genetic and environmental factors. Haploinsufficiency of the Coiled-coil and C2 domain containing 1A (Cc2d1a) gene is causally linked to ASD, and obesity has been associated with worse outcomes for ASD. High-fat diet (HFD) feeding leads to the development of obesity and metabolic dysfunction; however, the effect of HFD on pre-existing autistic-like phenotypes remains to be clarified. Here, we report that male Cc2d1a conditional knockout (cKO) mice fed with HFD, from weaning onwards and throughout the experimental period, show a marked aggravation in autistic-like phenotypes, manifested in increased restricted repetitive behaviors and impaired performance in the preference for social novelty, but not in sociability and cognitive impairments assessed using the object location memory, novel object recognition, and Morris water maze tests. HFD feeding also results in increased numbers of reactive microglia and astrocytes, and exacerbates reductions in dendritic complexity and spine density of hippocampal CA1 pyramidal neurons. Furthermore, we demonstrate that chronic treatment with minocycline, a semisynthetic tetracycline-derived antibiotic, rescues the observed behavioral and morphological deficits in Cc2d1a cKO mice fed with HFD. Collectively, these findings highlight an aggravating role of HFD in pre-existing autistic-like phenotypes and suggest that minocycline treatment can alleviate abnormal neuronal morphology and behavioral symptoms associated with ASD resulted from the interplay between genetic and environmental risk factors.

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Diet, High-Fat; Disease Models, Animal; DNA-Binding Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Minocycline; Obesity; Social Behavior

Both hypothalamic microglial inflammation and melanocortin pathway dysfunction contribute to diet-induced obesity (DIO) pathogenesis. Previous studies involving models of altered microglial signaling demonstrate altered DIO susceptibility with corresponding POMC neuron cytological changes, suggesting a link between microglia and the melanocortin system. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling to protect against DIO. We performed metabolic analyses in high fat diet (HFD)-fed mice with targeted viral overexpression of CX3CL1 in the hypothalamus. Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. Hypothalamic overexpression of CX3CL1 increased leptin sensitivity and POMC gene expression, while reducing weight gain in animals fed an HFD. In electrophysiological recordings from hypothalamic slice preparations, HFD feeding was associated with reduced POMC neuron excitability and increased amplitude of inhibitory postsynaptic currents. Microglial silencing using minocycline or CX3CL1 treatment reversed these HFD-induced changes in POMC neuron electrophysiologic properties. Correspondingly, blockade of melanocortin receptor signaling in vivo prevented both the acute and chronic reduction in food intake and body weight mediated by CX3CL1. Our results show that suppressing microglial activation during HFD feeding reduces DIO susceptibility via a mechanism involving increased POMC neuron excitability and melanocortin signaling.

Topics: Animals; Chemokine CX3CL1; Diet, High-Fat; Hypothalamus; Leptin; Melanocortins; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Neurons; Obesity; Pro-Opiomelanocortin

Diets rich in sugar and saturated fat are associated with cognitive impairments in both humans and rodents with several potential mechanisms proposed. To test the involvement of diet-induced pro-inflammatory signaling, we exposed rats to a high-fat, high-sugar cafeteria diet, and administered the anti-inflammatory antibiotic minocycline. In the first experiment minocycline was coadministered across the diet, then in a second, independent cohort it was introduced following 4 weeks of cafeteria diet. Cafeteria diet impaired novel place recognition memory throughout the study. Minocycline not only prevented impairment in spatial recognition memory but also reversed impairment established in rats following 4 weeks cafeteria diet. Further, minocycline normalized diet-induced increases in hippocampal pro-inflammatory gene expression. No effects of minocycline were seen on adiposity or dietary intake across the experiments. Cafeteria diet and minocycline treatment significantly altered microbiome composition. The relative abundance of Desulfovibrio_OTU31, uniquely enriched in vehicle-treated cafeteria-fed rats, negatively and significantly correlated with spatial recognition memory. We developed a statistical model that accurately predicts spatial recognition memory based on Desulfovibrio_OTU31 relative abundance and fat mass. Thus, our results show that minocycline prevents and reverses a dietary-induced diet impairment in spatial recognition memory, and that spatial recognition performance is best predicted by changes in body composition and Desulfovibrio_OTU31, rather than changes in pro-inflammatory gene expression.

Topics: Animals; Diet, High-Fat; Microbiota; Minocycline; Obesity; Rats; Spatial Memory

The early-life environment is important in programming brain development, and metabolic disruptions at this time can have long-lasting effects. Previously, we have shown that rats overfed for the first 3 weeks of their neonatal life maintain obesity into adulthood. Neonatal overfeeding also leads to primed hypothalamic and hippocampal microglia that are hyper-responsive to an immune challenge in adulthood. However, whether this microglial priming contributes to the obese phenotype and whether it is possible to reverse either the obesity or the microglial priming are not clear. In the present study, we hypothesised that an intervention with minocycline during the juvenile period (postnatal day 21-42) would normalise both the microglial priming and obesity. To induce obesity in neonatal Wistar rats, we manipulated the litter sizes in which they were suckled, yielding litters of 12 (control-fed) or four (neonatally overfed). After weaning, we administered minocycline i.p. every second day for a 3-week period and examined body composition and microglial profiles 24 hours following an immune challenge with lipopolysaccharide. As demonstrated previously, neonatal overfeeding resulted in prolonged weight gain. However, minocycline failed to reverse this effect. Minocycline did reverse microglial priming in feeding-related regions of the hypothalamus, with minimal effects on pro-inflammatory cytokines and on microglial number and morphology in the hippocampus. Thus, the programming effect of neonatal overfeeding on microglial priming can be ameliorated by minocycline later in life. However, the persistent obesity seen after neonatal overfeeding is likely not driven by changes in hypothalamic inflammation and microglial activity.

Topics: Animals; Animals, Newborn; Cellular Reprogramming; Encephalitis; Female; Hypothalamus; Male; Microglia; Minocycline; Obesity; Overnutrition; Pregnancy; Rats; Rats, Wistar; Weight Gain

To compare the serum and urine pharmacokinetics (PK) of intravenous tigecycline in obese class III (obese-C3) adults with those in normal weight (NW) adults.. Obese-C3 (n = 8) and NW (n = 4) healthy adult volunteers received a single intravenous dose of 100 mg of tigecycline for 30 min. Serum (0-96 h) and urine (0-48 h) tigecycline concentrations were assayed by liquid chromatography with tandem mass spectrometry. Parametric population PK systems analyses were used to model the data and assess the effects of total body weight (TBW) on PK parameters. The area under the concentration-time curve extrapolated to infinity (AUC0-∞) was simulated to estimate the probability of AUC0-∞ : MIC target attainment and cumulative fraction of response (CFR) based on wild-type MIC distributions of select pathogens. Clinicaltrials.gov: NCT01560143.. The median (range) age, TBW and initial body mass index were 42 (20-50) years, 121 (61-160) kg and 43.8 (20.8-53.8) kg/m(2), respectively. The serum concentration-time profiles and exposures were similar in the obese-C3 and NW adults, with a mean urine recovery of 15.8% and 13.4%, respectively. The median (range) AUC0-∞ was 8.19 (6.12, 11.2) and 7.50 (6.78, 9.13) mg · h/L in the obese-C3 and NW groups, respectively. The clearance of tigecycline was not related to TBW. The CFR was calculated to be <90% against Acinetobacter baumannii, Enterobacter cloacae and Klebsiella pneumoniae for an AUC0-∞ : MIC target ≥ 6.96.. The serum and urine PK of tigecycline is similar in obese-C3 and NW healthy adults. A lower CFR is predicted against certain Gram-negative pathogens with the current standard tigecycline dosing regimen, irrespective of TBW.

Topics: Acinetobacter baumannii; Administration, Intravenous; Adult; Anti-Bacterial Agents; Chromatography, Liquid; Enterobacter cloacae; Female; Healthy Volunteers; Humans; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Obesity; Prospective Studies; Serum; Tandem Mass Spectrometry; Tigecycline; Urine; Young Adult

This prospective observational study aimed at describing prescription patterns of tigecycline and patient outcomes in 26 French intensive care units (ICU).. Data of consecutive cases of adult patients treated with tigecycline were collected from the initiation until 7 days after the end of treatment. Response to treatment was classified as success, failure or undetermined and analyses were presented according to severity (SOFA score <7 or ≥7). Survival was recorded at 28 days.. A total of 156 patients were included (64% male, age 60 ± 15 years). At inclusion, 53% had a SOFA score ≥7; 93% had received prior anti-infective agents. Tigecycline was given as first-line treatment in 47% of patients, mostly in combination (67%), for intra-abdominal (IAI 56%), skin and soft tissue (SSTI 19%) or other infections. A total of 76% of the treated infections were hospital-acquired. Bacteraemia was reported in 12% of patients. Median treatment duration was 9 days. Tigecycline was prematurely stopped in 42% patients. The global success rate was 60% at the end of treatment, and significantly higher with treatment duration more than 9 days (76 vs. 47%, P < 0.001). Success rate was 65% for patients alive at the end of treatment. Success rates tended to decrease with illness severity, immunosuppression, bacteraemia and obesity. Survival rate at day 28 was 85% in the whole cohort and significantly higher in the less severely ill patients (P < 0.001).. Tigecycline success rates appear comparable to those reported in clinical studies in ICU with severe infections. Tigecycline could be an alternative in ICU patients.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Critical Illness; Cross Infection; Drug Therapy, Combination; Female; France; Hospital Mortality; Humans; Immunocompromised Host; Infections; Intensive Care Units; Male; Middle Aged; Minocycline; Multivariate Analysis; Obesity; Patient Outcome Assessment; Prospective Studies; Severity of Illness Index; Tigecycline; Young Adult

Topics: Aged; Anti-Bacterial Agents; Carcinoma, Transitional Cell; Cross Infection; Drug Resistance, Multiple; Emphysema; Gram-Negative Bacterial Infections; Humans; Lupus Erythematosus, Discoid; Male; Minocycline; Obesity; Pneumonia, Bacterial; Pulmonary Disease, Chronic Obstructive; Stenotrophomonas maltophilia; Tigecycline; Urinary Bladder Neoplasms

We report two cases of bilateral papilledema in young women. The first patient was 15 years old and had experienced headaches and vomiting for one month, but no visual loss. Cerebral tomodensitometry results were normal, but lumbar puncture showed increased pressure and normal biology. Benign intracranial hypertension was diagnosed. Recent treatment with minocycline for acne vulgaris was the only etiology. Papilledema was totally regressed at 6 weeks, after interruption of the antibiotic treatment. A prescription of acetazolamide was added for a short period of 10 days. The second patient, aged 29 years, presented bilateral papilledema with severe visual loss, with vision limited to light perception with mydriasis of the right eye. Lumbar puncture was not indicated because of a hypophyseal microadenoma revealed on MRI investigation. No other associated abnormalities were observed, in particular, no cerebral sinus thrombosis. Corticotherapy using prednisolone for 72 hours had no clinical effect. Fast visual recovery was obtained with intravenous acetazolamide therapy and was completely resolved at 2 months. Right visual field defects persisted. Minocycline and obesity are recognized as precipitating factors in pseudotumor cerebri syndrome. The literature advocates consideration of surgical treatment by optic nerve sheath fenestration if antiedematous treatment has no effect and the eye is nearly blind.

Topics: Acetazolamide; Adolescent; Adult; Anti-Bacterial Agents; Carbonic Anhydrase Inhibitors; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Injections, Intravenous; Intracranial Hypertension; Minocycline; Obesity; Papilledema; Pseudotumor Cerebri; Time Factors; Visual Acuity