self-administration-of-drugs-in-mouse-models-of-feeding-and-obesity

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 ...

University of California San Diego

Total amino acid (AA) restriction promotes hyperphagia and energy expenditure. We determined whether (i) methionine restriction mimics the effects of total AA restriction, (ii) methionine supplementation attenuates these responses, and iii) sympathetic signaling mediates such effects. Rats were injected with either vehicle (V) or 6-hydroxydopamine (S) to induce chemical sympathectomy, and then randomized to four diets: 16% AA (16AA), 5% AA (5AA), 16% AA-methionine (16AA-Met), and 5% AA+methionine (5AA+Met). Propranolol or ondansetron were injected to examine the role of sympathetic and serotonergic signaling, respectively. 5AA, 5AA+Met, and 16AA-Met increased the food conversion rate for 1⁻3 weeks in the V and S groups, and increased mean energy expenditure in V group,; the magnitude of these changes was attenuated in the S group. Propranolol decreased the energy expenditure of V16AA, V5AA, and V5AA+Met and of S5AA, S5AA+Met, and S16AA-Met, whereas ondansetron decreased the energy expenditure in only the S groups. Compared to 16AA, the other V groups had reduced body weights from days 7⁻11 onwards and decreased lean masses throughout the study and the other S groups had decreased body weights and lean masses from day 14 onwards. Total AA restriction enhanced the energy expenditure and reduced the weight and lean mass; these effects were partly recapitulated by methionine restriction and were sympathetically mediated.

Methionine Restriction Partly Recapitulates the Sympathetically Mediated Enhanced Energy Expenditure Induced by Total Amino Acid Restriction in Rats.

Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice.

While both men and women gain weight as a side effect of antipsychotic (AP) treatment, studies in mice have found only female mice are susceptible to weight gain. Therefore, to we set out to identify a strain of male mice that gain significant weight in response to APs which could better model AP-induced weight gain observed in humans. These studies determined that male Balb/c mice developed late onset olanzapine-induced weight gain. Patients often take APs for many years and thus understanding AP-mediated changes in food intake, energy expenditure and body weight regulation is particularly important.

Susceptibility of male wild type mouse strains to antipsychotic-induced 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.

Article	Year
Methionine Restriction Partly Recapitulates the Sympathetically Mediated Enhanced Energy Expenditure Induced by Total Amino Acid Restriction in Rats. Nutrients\| PubMed ID: 30917593	2019
Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice. Scientific reports\| PubMed ID: 31611602	2019
Susceptibility of male wild type mouse strains to antipsychotic-induced weight gain. Physiology & behavior\| PubMed ID: 32156556	2020
Metabolomic profiles associated with a mouse model of antipsychotic-induced food intake and weight gain. Scientific reports\| PubMed ID: 33122657	2020

Rizaldy C. Zapata

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