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1.
Behav Brain Res ; 423: 113773, 2022 04 09.
Article in English | MEDLINE | ID: mdl-35101456

ABSTRACT

Despite the prevalence of anxiety disorders, the molecular identity of neural circuits underlying anxiety remains unclear. The lateral hypothalamus (LH) is one brain region implicated in the regulation of anxiety, and our recent data found that chemogenetic activation of LH galanin neurons attenuated the stress response to a novel environment as measured by the marble burying test. Thus, we hypothesize that LH galanin neurons may contribute to anxiety-related behavior. We used chemogenetics and fiber photometry to test the ability of LH galanin neurons to influence anxiety and stress-related behavior. Chemogenetic activation of LH galanin neurons significantly decreased anxiety-like behavior in the elevated plus maze, open field test, and light dark test. However, LH galanin activation did not alter restraint stress induced HPA activation or freezing behavior in the fear conditioning paradigm. In vivo calcium monitoring by fiber photometry indicated that LH galanin neurons were activated by anxiogenic and/or stressful stimuli including tail suspension, novel mouse interaction, and predator odor. Further, in a fear conditioning task, calcium transients strongly increased during foot shock, but were not affected by the unconditioned stimulus tone. These data indicate that LH galanin neurons both respond to and modulate anxiety, with no influence on stress induced HPA activation or fear behaviors. Further investigation of LH galanin circuitry and functional mediators of behavioral output may offer a more refined pharmacological target as an alternative to first-line broad pharmacotherapies such as benzodiazepines.


Subject(s)
Anxiety/metabolism , Behavior, Animal/physiology , Galanin/metabolism , Hypothalamic Area, Lateral/metabolism , Neurons/metabolism , Stress, Psychological/metabolism , Animals , Conditioning, Classical/physiology , Disease Models, Animal , Fear/physiology , Mice , Mice, Inbred C57BL
2.
Sci Rep ; 9(1): 7881, 2019 05 27.
Article in English | MEDLINE | ID: mdl-31133715

ABSTRACT

Gastric bypass surgery is the most effective treatment and is often the only option for subjects with severe obesity. However, investigation of critical molecular mechanisms involved has been hindered by confounding of specific effects of surgery and side effects associated with acute surgical trauma. Here, we dissociate the two components by carrying out surgery in the lean state and testing its effectiveness to prevent diet-induced obesity later in life. Body weight and composition of female mice with RYGB performed at 6 weeks of age were not significantly different from sham-operated and age-matched non-surgical mice at the time of high-fat diet exposure 12 weeks after surgery. These female mice were completely protected from high-fat diet-induced obesity and accompanying metabolic impairments for up to 50 weeks. Similar effects were seen in male mice subjected to RYGB at 5-6 weeks, although growth was slightly inhibited and protection from diet-induced obesity was less complete. The findings confirm that RYGB does not indiscriminately lower body weight but specifically prevents excessive diet-induced obesity and ensuing metabolic impairments. This prevention of obesity model should be crucial for identifying the molecular mechanisms underlying gastric bypass surgery.


Subject(s)
Diet, High-Fat/adverse effects , Gastric Bypass , Obesity/etiology , Obesity/prevention & control , Aging , Animals , Blood Glucose/analysis , Body Composition , Body Weight , Eating , Energy Metabolism , Male , Mice , Mice, Inbred C57BL , Obesity/blood , Obesity/metabolism
3.
Obes Surg ; 28(10): 3227-3236, 2018 10.
Article in English | MEDLINE | ID: mdl-29770924

ABSTRACT

BACKGROUND AND PURPOSE: Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective treatments for obesity and type 2 diabetes. Despite this, the mechanisms through which it acts are still not well understood. Bile acid signaling through the transmembrane G-protein-coupled receptor TGR5 has been shown to have significant effects on metabolism and has recently been reported to be necessary for the full effects of vertical sleeve gastrectomy (VSG), a bariatric surgery with similar effects to RYGB. The goal of the current study is therefore to investigate the role of bile acid signaling through TGR5 to see if it is necessary to obtain the full effects of RYGB. METHODS: High-fat diet-induced obese TGR5-/- and wildtype mice (WT) were subjected to RYGB, sham surgery, or weight matching (WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance, insulin sensitivity, and liver weight were measured. RESULTS: Although the difference in fat mass 20 weeks after surgery between RYGB and sham-operated mice was slightly reduced in TGR5-/- mice when compared to wildtype mice, loss of body weight and fat mass from preoperative levels, reduction of food intake, increase of energy expenditure, and improvement in glycemic control were similar in the two genotypes. Furthermore, improvements in glycemic control were similar in non-surgical mice weight-matched to RYGB. CONCLUSIONS: We conclude that bile acid signaling through TGR5 is not required for the beneficial effects of RYGB in the mouse and that RYGB and VSG may achieve their similar beneficial effects through different mechanisms.


Subject(s)
Gastric Bypass/methods , Obesity/metabolism , Obesity/surgery , Receptors, G-Protein-Coupled/genetics , Weight Loss/physiology , Anastomosis, Roux-en-Y/methods , Animals , Blood Glucose/metabolism , Body Composition/genetics , Diet, High-Fat , Eating , Energy Metabolism/genetics , Insulin Resistance/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/etiology , Obesity/pathology , Weight Loss/genetics
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