Targeting Clic1 for the treatment of obesity: A novel therapeutic strategy to reduce food intake and body weight.

OBJECTIVE: Despite great advances in obesity therapeutics in recent years, there is still a need to identify additional therapeutic targets for the treatment of this disease. We previously discovered a signature of genes, including Chloride intracellular channel 1 (Clic1), whose expression was associated with drug-induced weight gain, and in these studies, we assess the effect of Clic1 inhibition on food intake and body weight in mice. METHODS: We studied the impact of Clic1 inhibition in mouse models of binge-eating, diet-induced obese mice and genetic models of obesity (Magel2 KO mice). RESULTS: Clic1 knockout (KO) mice ate significantly less and had a lower body weight than WT littermates when either fed chow or high fat diet. Furthermore, pharmacological inhibition of Clic1 in diet-induced obese mice resulted in suppression of food intake and promoted highly efficacious weight loss. Clic1 inhibition also reduced food intake in binge-eating models and hyperphagic Magel2 KO mice. We observed that chronic obesity resulted in a significant change in subcellular localization of Clic1 with an increased ratio of Clic1 in the membrane in the obese state. These observations provide a novel therapeutic strategy to block Clic1 translocation as a potential mechanism to reduce food intake and lower body weight. CONCLUSIONS: These studies attribute a novel role of Clic1 as a driver of food intake and overconsumption. In summary, we have identified hypothalamic expression of Clic1 plays a key role in food intake, providing a novel therapeutic target to treat overconsumption that is the root cause of modern obesity.

Antipsychotic-induced weight gain and metabolic effects show diurnal dependence and are reversible with time restricted feeding.

Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side-effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side-effects is not well-known. We hypothesized that time of AP dosing impacts the development of metabolic side-effects. Weight gain and metabolic side-effects were compared in C57Bl/6 mice and humans dosed with APs in either the morning or evening. In mice, AP dosing at the start of the light cycle/rest period (AM) resulted in significant increase in food intake and weight gain compared with equivalent dose before the onset of darkness/active period (PM). Time of AP dosing also impacted circadian gene expression, metabolic hormones and inflammatory pathways and their diurnal expression patterns. We also conducted a retrospective examination of weight and metabolic outcomes in patients who received risperidone (RIS) for the treatment of serious mental illness and observed a significant association between time of dosing and severity of RIS-induced metabolic side-effects. Time restricted feeding (TRF) has been shown in both mouse and some human studies to be an effective therapeutic intervention against obesity and metabolic disease. We demonstrate, for the first time, that TRF is an effective intervention to reduce AP-induced metabolic side effects in mice. These studies identify highly effective and translatable interventions with potential to mitigate AP-induced metabolic side effects.

Adipocytes control food intake and weight regain via Vacuolar-type H+ ATPase.

Energy metabolism becomes dysregulated in individuals with obesity and many of these changes persist after weight loss and likely play a role in weight regain. In these studies, we use a mouse model of diet-induced obesity and weight loss to study the transcriptional memory of obesity. We found that the 'metabolic memory' of obesity is predominantly localized in adipocytes. Utilizing a C. elegans-based food intake assay, we identify 'metabolic memory' genes that play a role in food intake regulation. We show that expression of ATP6v0a1, a subunit of V-ATPase, is significantly induced in both obese mouse and human adipocytes that persists after weight loss. C. elegans mutants deficient in Atp6v0A1/unc32 eat less than WT controls. Adipocyte-specific Atp6v0a1 knockout mice have reduced food intake and gain less weight in response to HFD. Pharmacological disruption of V-ATPase assembly leads to decreased food intake and less weight re-gain. In summary, using a series of genetic tools from invertebrates to vertebrates, we identify ATP6v0a1 as a regulator of peripheral metabolic memory, providing a potential target for regulation of food intake, weight loss maintenance and the treatment of obesity.

Conserved immunomodulatory transcriptional networks underlie antipsychotic-induced weight gain.

Although antipsychotics, such as olanzapine, are effective in the management of psychiatric conditions, some patients experience excessive antipsychotic-induced weight gain (AIWG). To illuminate pathways underlying AIWG, we compared baseline blood gene expression profiles in two cohorts of mice that were either prone (AIWG-P) or resistant (AIWG-R) to weight gain in response to olanzapine treatment for two weeks. We found that transcripts elevated in AIWG-P mice relative to AIWG-R are enriched for high-confidence transcriptional targets of numerous inflammatory and immunomodulatory signaling nodes. Moreover, these nodes are themselves enriched for genes whose disruption in mice is associated with reduced body fat mass and slow postnatal weight gain. In addition, we identified gene expression profiles in common between our mouse AIWG-P gene set and an existing human AIWG-P gene set whose regulation by immunomodulatory transcription factors is highly conserved between species. Finally, we identified striking convergence between mouse AIWG-P transcriptional regulatory networks and those associated with body weight and body mass index in humans. We propose that immunomodulatory transcriptional networks drive AIWG, and that these networks have broader conserved roles in whole body-metabolism.

Self-Administration of Drugs in Mouse Models of Feeding and Obesity.

Preclinical studies in mice often rely on invasive protocols, such as injections or oral gavage, to deliver drugs. These stressful routes of administration have significant effects on important metabolic parameters including food intake and body weight. Although an attractive option to circumvent this is to compound the drug in rodent food or dissolve it in water, these approaches also have limitations as they are affected by drug stability at room temperature for extended periods of time, the drug's solubility in water, and that the dosing is highly dependent on timing of food or water intake. The constant availability of the drug also limits translational relevance on how drugs are administered to patients. To overcome these limitations, drugs can be mixed with highly palatable food, such as peanut butter, allowing mice to self-administer compounds. Mice reliably and reproducibly consume the drug/peanut butter pellet in a short time frame. This approach facilitates a delivery approach with minimal stress compared with an injection or gavage. This protocol demonstrates the approach of drug preparation, animal acclimatization to placebo delivery, and drug delivery. The implications of this approach are discussed in studies related to timing of drug administration and the circadian rhythm.