lithium-chloride and Obesity

Wnt/β-catenin signaling pathway is implicated in the etiology and progression of metabolic disorders. Although lines of genetic evidence suggest that blockage of this pathway yields favorable outcomes in treating such ailments, few inhibitors have been used to validate the promising genetic findings. Here, we synthesized and characterized a novel class of triazole-based Wnt/β-catenin signaling inhibitors and assessed their effects on energy metabolism. One of the top inhibitors, compound 3a, promoted Axin stabilization, which led to the proteasome degradation of β-catenin and subsequent inhibition of the Wnt/β-catenin signaling in cells. Treatment of hepatocytes and high fat diet-fed mice with compound 3a resulted in significantly decreased hepatic lipid accumulation. Moreover, compound 3a improved glucose tolerance of high fat diet-fed mice without noticeable toxicity, while downregulating the genes involved in the glucose and fatty acid anabolisms. The new inhibitors are expected to be further developed for the treatment of metabolic disorders.

Topics: Animals; beta Catenin; Diet, High-Fat; Glucose; Glucose Tolerance Test; HEK293 Cells; Hepatocytes; Humans; Lipid Metabolism; Lithium Chloride; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Structure-Activity Relationship; Triazoles; Wnt Signaling Pathway

The 5-HT

Topics: Allosteric Regulation; Animals; Anti-Obesity Agents; Appetite Regulation; Humans; Male; Mice; Obesity; Pyridines; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Agonists; Taste Perception

Recent evidence suggests that GSK3 activity is chondroprotective in osteoarthritis (OA), but at the same time, its inactivation has been proposed as an anti-inflammatory therapeutic option. Here we evaluated the extent of GSK3β inactivation in vivo in OA knee cartilage and the molecular events downstream GSK3β inactivation in vitro to assess their contribution to cell senescence and hypertrophy.. In vivo level of phosphorylated GSK3β was analyzed in cartilage and oxidative damage was assessed by 8-oxo-deoxyguanosine staining. The in vitro effects of GSK3β inactivation (using either LiCl or SB216763) were evaluated on proliferating primary human chondrocytes by combined confocal microscopy analysis of Mitotracker staining and reactive oxygen species (ROS) production (2',7'-dichlorofluorescin diacetate staining). Downstream effects on DNA damage and senescence were investigated by western blot (γH2AX, GADD45β and p21), flow cytometric analysis of cell cycle and light scattering properties, quantitative assessment of senescence associated β galactosidase activity, and PAS staining.. In vivo chondrocytes from obese OA patients showed higher levels of phosphorylated GSK3β, oxidative damage and expression of GADD45β and p21, in comparison with chondrocytes of nonobese OA patients. LiCl mediated GSK3β inactivation in vitro resulted in increased mitochondrial ROS production, responsible for reduced cell proliferation, S phase transient arrest, and increase in cell senescence, size and granularity. Collectively, western blot data supported the occurrence of a DNA damage response leading to cellular senescence with increase in γH2AX, GADD45β and p21. Moreover, LiCl boosted 8-oxo-dG staining, expression of IKKα and MMP-10.. In articular chondrocytes, GSK3β activity is required for the maintenance of proliferative potential and phenotype. Conversely, GSK3β inactivation, although preserving chondrocyte survival, results in functional impairment via induction of hypertrophy and senescence. Indeed, GSK3β inactivation is responsible for ROS production, triggering oxidative stress and DNA damage response.

Topics: Cell Proliferation; Cell Size; Cells, Cultured; Cellular Senescence; Chondrocytes; DNA Damage; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Indoles; Lithium Chloride; Maleimides; Obesity; Osteoarthritis, Knee; Oxidative Stress; Phosphorylation

Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders. Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3β. The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. Stabilization of glycogen synthase and β-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation. Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level. In vitro and in vivo effects were accompanied by upregulation of β-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism. From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiposity; Aminophenols; Animals; Anti-Obesity Agents; beta Catenin; Body Weight; Cell Differentiation; Chromones; Glycogen Synthase Kinase 3; HEK293 Cells; Hep G2 Cells; Humans; Lipid Metabolism; Lithium Chloride; Male; Maleimides; Mice; Mice, Inbred C57BL; Obesity; Protein Stability; Thiazoles

Topics: Adrenergic alpha-Agonists; Antimanic Agents; Antipsychotic Agents; Aripiprazole; Asthma; Attention Deficit Disorder with Hyperactivity; Cardiovascular Diseases; Chest Pain; Child; Dyskinesia, Drug-Induced; Family; Female; Guanfacine; Humans; Lithium Chloride; Male; Mood Disorders; Neuropsychological Tests; Obesity; Paroxetine; Piperazines; Polypharmacy; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Agitation; Quinolones; Selective Serotonin Reuptake Inhibitors; Smoking; Social Environment

Extreme obesity slowly develops in female rats over the months following seizures induced by a single systemic injection of lithium and pilocarpine if the resulting limbic seizures are treated with the atypical neuroleptic acepromazine (but not with ketamine). To discern the contributions from food consumption, water consumption, and (daytime and nighttime) activity to this weight gain, these behaviors were monitored for 4 months, about 2 months after seizure induction. The results indicated that the rats that underwent the obesity procedure exhibited 50% heavier body weights and consumed 42% more food than the reference group, which included rats that had been induced to seize but treated with ketamine. There were no statistically significant differences between groups with respect to either water consumption or (daytime or nighttime) activity. Factor analyses of data for individual rats verified the dissociation between activity and weight gain for the obese rats. The results suggest that the progressive weight gains are centrally mediated and are not secondary to diminished activity or altered fluid consumption.

Topics: Acepromazine; Analysis of Variance; Animals; Antipsychotic Agents; Body Weight; Disease Models, Animal; Drinking; Eating; Epilepsy; Female; Lithium Chloride; Obesity; Pilocarpine; Rats; Rats, Wistar; Weight Gain

The worldwide prevalence of obesity is increasing at an alarming rate, along with the associated increased rates of type 2 diabetes, heart disease, and some cancers. While efforts to address environmental factors responsible for the recent epidemic must continue, investigation into the anorectic functions of potential molecules we present here, such as apolipoprotein (apo)E, offers exciting possibilities for future development of successful anti-obesity therapies.. Changes in feeding behavior after intracerebroventricular injection of apoE, the regulation of hypothalamic apoE gene expression by energy status, and the interaction of hypothalamic apoE with other neuropeptides were studied.. Intracerebroventricular apoE significantly decreased food intake without causing malaise, whereas intracerebroventricular infusion of apoE antiserum stimulated feeding, implying that endogenous apoE tonically inhibits food intake. Consistent with this, apoE was present in the hypothalamus, a brain site intimately involved in the integration of signals for energy homeostasis. Fasted rats exhibited significantly decreased apoE gene expression in the hypothalamus, and refeeding of these rats for 4 h evoked a significant increase of hypothalamic apoE mRNA levels. Both genetically obese (ob/ob) mice and rats with high-fat diet-induced obesity had significantly reduced hypothalamic apoE mRNA levels compared with their lean control counterparts, suggesting that decreased apoE may contribute to hyperphagia in these obese animals. Additionally, apoE-stimulated hypothalamic proopiomelanocortin gene expression and SHU9119, a melanocortin 3/4 receptor antagonist, attenuated the inhibitory function of apoE on feeding.. These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus.

Topics: Animals; Antibodies; Apolipoproteins E; Blotting, Western; Body Weight; Brain; Dietary Fats; Eating; Fasting; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Lithium Chloride; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Obese; Neuropeptides; Obesity; Rats; Rats, Long-Evans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Mutations in the tyrosine kinase receptor trkB or in one of its natural ligands, brain-derived neurotrophic factor (BDNF), lead to severe hyperphagia and obesity in rodents and/or humans. Here, we show that peripheral administration of neurotrophin-4 (NT4), the second natural ligand for trkB, suppresses appetite and body weight in a dose-dependent manner in several murine models of obesity. NT4 treatment increased lipolysis, reduced body fat content and leptin, and elicited long-lasting amelioration of hypertriglyceridemia and hyperglycemia. After treatment termination, body weight gradually recovered to control levels in obese mice with functional leptin receptor. A single intrahypothalamic application of minute amounts of NT4 or an agonist trkB antibody also reduced food intake and body weight in mice. Taken together with the genetic evidence, our findings support the concept that trkB signaling, which originates in the hypothalamus, directly modulates appetite, metabolism, and taste preference downstream of the leptin and melanocortin 4 receptor. The trkB agonists mediate anorexic and weight-reducing effects independent of stress induction, visceral discomfort, or pain sensitization and thus emerge as a potential therapeutic for metabolic disorders.

Topics: Animals; Body Weight; Disease Models, Animal; Eating; Energy Metabolism; Glucose; Homeostasis; Leptin; Lithium Chloride; Male; Melanocortins; Mice; Mice, Inbred C57BL; Mice, Obese; Nerve Growth Factors; Obesity; Rats; Rats, Sprague-Dawley; Receptor, trkB; Receptors, Leptin; Taste; Triglycerides

A series of brief-access (15s) behavioral assays following the formation of a conditioned taste aversion (CTA) to linoleic acid were performed in order to follow up on observations showing differences in the chemosensory responses to dietary fat in obesity-prone (Osborne-Mendel [O-M]) and obesity-resistant (S5B/Pl) rat strains. Strong aversions to linoleic acid (conditioned stimulus 100 microM) were generated in both O-M and S5B/Pl rats to concentrations as low as 2.5 microM. Observed strain differences were in contrast to expectations based upon electrophysiological studies previously showing greater fatty acid-induced inhibition of delayed rectifying K+ channels in S5B/Pl rats. In the CTA assays, the O-M rats showed aversions at lower fatty acid concentrations with more resistance to extinction in brief-access orosensory tests, suggesting that the obesity-prone strain may be more sensitive in the detection and subsequent avoidance of linoleic acid than the obesity-resistant strain. The independent variable of sex produced even greater differences in the avoidance of linoleic acid following conditioning than the effects of strain. Female rats of both strains were significantly more sensitive to fatty acids, showed greater cross-generalization from linoleic to oleic acid, and showed greater avoidance of linoleic acid than male counterparts. These findings suggest genetic influences on yet to be identified mechanisms potentially within the gustatory system that affect the sensitivity to detect the fatty acid chemicals found in dietary fat during brief-access orosensory testing.

Topics: Administration, Oral; Animals; Fatty Acids; Female; Lithium Chloride; Male; Obesity; Rats; Rats, Inbred Strains; Sex Characteristics; Sodium Chloride; Species Specificity; Stimulation, Chemical; Taste

The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732's peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long-Evans Tokushima Otsuka and Otsuka Long-Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114.8 +/- 13.4 g vs 170.7 +/- 20.6 g, 7.9 +/- 0.5% decrease vs 0.3 +/- 2.2% decrease; in treated OLETF rat versus control OLETF rat, P < 0.01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.

Topics: Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Size; Cinnamates; Cyclohexanes; Eating; Epoxy Compounds; Hypothalamus; Lithium Chloride; Male; Mice; Mice, Obese; Neuropeptides; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Rats; Rats, Inbred OLETF; Sesquiterpenes; Taste

To evaluate the effectiveness of lithium augmentation of topiramate on mood symptoms, binge eating behavior, and body weight in obese bipolar patients with binge eating disorder (BED) seeking weight management.. We conducted a naturalistic study of 12 consecutive outpatients with bipolar disorders, BED, and obesity who received lithium augmentation for mood instability during the course of topiramate-based pharmacotherapy for obesity and BED. Lithium was added to topiramate (mean dose 514 mg i.d.) and titrated to a mean dose of 1009 mg i.d. (mean plasma concentration 0.7 mmol/L). Treatment response was assessed by comparing changes in clinical severity scales for mood and eating disorders, weekly binge eating frequency, and weight for the 2 months before and the first 2 months during lithium treatment.. A statistically significant improvement in global severity of mood symptoms was observed after as compared to before lithium augmentation. Statistically insignificant reductions in weight and in binge frequency and severity were also observed after lithium addition.. Optimal weight loss treatment in obese patients with comorbid bipolar and BEDs may require stabilization of mood. The combination of lithium and topiramate may have a role in the management of this difficult-to-treat population.

Topics: Adult; Anti-Obesity Agents; Antimanic Agents; Bipolar Disorder; Body Mass Index; Body Weight; Bulimia Nervosa; Comorbidity; Drug Interactions; Female; Follow-Up Studies; Fructose; Humans; Lithium Chloride; Male; Middle Aged; Obesity; Severity of Illness Index; Statistics, Nonparametric; Surveys and Questionnaires; Topiramate

Lithium's impact on glucose metabolism was compared with that of insulin in isolated rat soleus muscle. Lithium chloride (20 mmol/l) induced a 4.8-fold more pronounced increment over basal glycogen synthase activity than insulin (10 nmol/l) (nmol UDP-glucose into glycogen in synthase activity assay.g-1.min-1: lithium, +22.1 +/- 1.8 vs. insulin, +4.6 +/- 3.9; P < 0.01). In parallel, lithium was less efficient than insulin in stimulating glucose transport (counts per minute 2-deoxy-D-[3H]glucose.mg-1.h-1: lithium, +211 +/- 19 vs. insulin, +311 +/- 57; P < 0.05) and lactate release (mumol.g-1.h-1: lithium, +1.0 +/- 0.5 vs. insulin, +3.9 +/- 0.5; P < 0.01), and similar increments were induced in glycogen synthesis (mumol glucose into glycogen.g-1.h-1: lithium, +3.32 +/- 0.43 vs. insulin, +3.46 +/- 0.47; not significant). Full additivity of glycogenic effects and divergent dependency on phosphatidylinositol 3-kinase activation provided further evidence for different mechanisms of action. In muscle from insulin-resistant obese Zucker rats (fa/fa), failure of lithium to reverse deficits in glucose metabolism suggested a primary deficit in muscle glucose uptake rather than glycogen synthesis. Hence lithium distinctly stimulates glycogen synthase activity in skeletal muscle and may therefore be regarded as a candidate for the treatment of disorders associated with primary deficits in the glycogenic pathway.

Topics: Androstadienes; Animals; Biological Transport; Cytochalasin B; Dantrolene; Deoxyglucose; Glucose; Glycogen; Glycogen Synthase; In Vitro Techniques; Insulin; Insulin-Like Growth Factor I; Isoproterenol; Kinetics; Lactates; Lithium Chloride; Male; Muscle, Skeletal; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; Wortmannin

The development of a conditioned taste aversion (CTA) was assessed in rats made hyperphagic with parasagittal knife cuts in the ventromedial hypothalamus (VMH). The animals were water deprived and presented with a .1% saccharin solution paired with injections of either lithium chloride or sodium chloride. In Experiment 1, VMH rats tested at a nonobese weight level did not differ from sham-operated control rats in the acquisition and extinction of the CTA. In Experiment 2, moderately obese VMH rats displayed a stronger CTA than did sham-operated control rats as evidenced by a slower rate of extinction. This effect was not due to the higher absolute dose of LiCl given to the obese VMH rats. A second group of obese VMH rats given an amount of LiCl equivalent to that given to the control rats also displayed retarded extinction of the CTA. The results of these experiments demonstrate that hyperphagia-inducing knife cuts do not alter aversive taste conditioning in rats but that hypothalamic obesity does enhance conditioned taste aversions. This may reflect an obesity-induced suppression in appetitive motivation.

Topics: Animals; Body Weight; Chlorides; Conditioning, Classical; Extinction, Psychological; Female; Hypothalamus, Middle; Lithium; Lithium Chloride; Obesity; Rats; Rats, Inbred Strains; Saccharin; Sodium Chloride; Taste; Water Deprivation