minocycline and Weight-Gain

Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON + MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ + MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.

Topics: Animals; Anti-Bacterial Agents; Antipsychotic Agents; Eating; Female; Hyperphagia; Hypothalamus; Metabolome; Mice; Mice, Inbred C57BL; Minocycline; Olanzapine; Weight Gain

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

Diabetes is a chronic disease associated with depression whose pathophysiological mechanisms that associate these conditions are not fully elucidated. However, the activation of the indoleamine-2,3-dioxygenase (IDO), an enzyme that participate of the tryptophan metabolism leading to a decrease of serotonin (5-HT) levels and whose expression is associated with an immune system activation, has been proposed as a common mechanism that links depression and diabetes. To test this hypothesis, diabetic (DBT) and normoglycemic (NGL) groups had the cytokines (TNFα, IL-1β, and IL-6) and 5-HT and norepinephrine (NE) levels in the hippocampus (HIP) evaluated. Moreover, the effect of the selective serotonin reuptake inhibitor fluoxetine (FLX), IDO direct inhibitor 1-methyl-tryptophan (1-MT), anti-inflammatory and IDO indirect inhibitor minocycline (MINO), or non-selective cyclooxygenase inhibitor ibuprofen (IBU) was evaluated in DBT rats submitted to the modified forced swimming test (MFST). After the behavioral test, the HIP was obtained for IDO expression by Western blotting analysis. DBT rats exhibited a significant increase in HIP levels of TNFα, IL-1β, and IL-6 and a decrease in HIP 5-HT and NA levels. They also presented a depressive-like behavior which was reverted by all employed treatments. Interestingly, treatment with MINO, IBU, or FLX but not with 1-MT reduced the increased IDO expression in the HIP from DBT animals. Taken together, our data support our hypothesis that neuroinflammation in the HIP followed by IDO activation with a consequent decrease in the 5-HT levels can be a possible pathophysiological mechanism that links depression to diabetes.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Blood Glucose; Cytokines; Depression; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Fluoxetine; Hippocampus; Ibuprofen; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation Mediators; Kynurenine; Male; Minocycline; Molecular Targeted Therapy; Motor Activity; Norepinephrine; Rats, Wistar; Serotonin; Swimming; Tryptophan; Weight Gain