Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat

Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe the in vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neurons to exterosensory cues but fails to rescue their sensitivity to gastrointestinal hormones or nutrients. These findings reveal that obesity triggers broad dysregulation of hypothalamic hunger neurons that is incompletely reversed by weight loss and may contribute to the difficulty of maintaining a reduced weight.

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Replacing a Palatable High-Fat Diet with a Low-Fat Alternative Heightens κ-Opioid Receptor Control over Nucleus Accumbens Dopamine

Nutrients ◽

10.3390/nu13072341 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2341

Author(s):

Conner W. Wallace ◽

Nari S. Beatty ◽

Sarah A. Hutcherson ◽

Heather A. Emmons ◽

Madison C. Loudermilt ◽

...

Keyword(s):

Weight Loss ◽

Nucleus Accumbens ◽

High Fat Diet ◽

Elevated Plus Maze ◽

High Fat ◽

Food Cravings ◽

Fast Scan Cyclic Voltammetry ◽

Diet Induced Obesity ◽

Plus Maze ◽

Weight Loss Interventions

Diet-induced obesity reduces dopaminergic neurotransmission in the nucleus accumbens (NAc), and stressful weight loss interventions could promote cravings for palatable foods high in fat and sugar that stimulate dopamine. Activation of κ-opioid receptors (KORs) reduces synaptic dopamine, but contribution of KORs to lower dopamine tone after dietary changes is unknown. Therefore, the purpose of this study was to determine the function of KORs in C57BL/6 mice that consumed a 60% high-fat diet (HFD) for six weeks followed by replacement of HFD with a control 10% fat diet for one day or one week. HFD replacement induced voluntary caloric restriction and weight loss. However, fast-scan cyclic voltammetry revealed no differences in baseline dopamine parameters, whereas sex effects were revealed during KOR stimulation. NAc core dopamine release was reduced by KOR agonism after one day of HFD replacement in females but after one week of HFD replacement in males. Further, elevated plus-maze testing revealed no diet effects during HFD replacement on overt anxiety. These results suggest that KORs reduce NAc dopamine tone and increase food-related anxiety during dietary weight loss interventions that could subsequently promote palatable food cravings and inhibit weight loss.

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Viola mandshurica ethanolic extract prevents high-fat-diet-induced obesity in mice by activating AMP-activated protein kinase

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2014.04.028 ◽

2014 ◽

Vol 38 (1) ◽

pp. 41-50 ◽

Cited By ~ 10

Author(s):

Yoon-Young Sung ◽

Dong-Seon Kim ◽

Ho Kyoung Kim

Keyword(s):

Protein Kinase ◽

High Fat Diet ◽

Ethanolic Extract ◽

High Fat ◽

Diet Induced Obesity ◽

Obesity In Mice ◽

Amp Activated Protein Kinase

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An ursolic acid-enriched Cynomorium songarium extract attenuates high fat diet-induced obesity in mice possibly through mitochondrial uncoupling

Journal of Functional Foods ◽

10.1016/j.jff.2014.04.021 ◽

2014 ◽

Vol 9 ◽

pp. 211-224 ◽

Cited By ~ 7

Author(s):

Jihang Chen ◽

Hoi Shan Wong ◽

Hoi Yan Leung ◽

Pou Kuan Leong ◽

Wing Man Chan ◽

...

Keyword(s):

Ursolic Acid ◽

High Fat Diet ◽

High Fat ◽

Mitochondrial Uncoupling ◽

Diet Induced Obesity ◽

Obesity In Mice

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α-Methyl-L-Tryptophan as a Weight-Loss Agent in Multiple Models of Obesity in Mice

Biochemical Journal ◽

10.1042/bcj20210100 ◽

2021 ◽

Author(s):

Sathish Sivaprakasam ◽

Sabarish Ramachandran ◽

Mohd Omar Faruk Sikder ◽

Yangzom Doma Bhutia ◽

Mitchell Wachtel ◽

...

Keyword(s):

Weight Loss ◽

High Fat Diet ◽

Amino Acid Profile ◽

Normal Diet ◽

The Body ◽

Multiple Models ◽

High Fat ◽

Liver And Kidney ◽

Obesity In Mice ◽

Treatment Of Obesity

a-Methyl-L-tryptophan (a-MLT) is currently in use as a tracer in its 11C-labeled form to monitor the health of serotonergic neurons in humans. In the present study, we found this compound to function as an effective weight-loss agent at pharmacological doses in multiple models of obesity in mice. The drug was able to reduce the body weight when given orally in drinking water (1 mg/ml) in three different models of obesity: normal mice on high-fat diet, Slc6a14-null mice on high-fat diet, and ob/ob mice on normal diet. Only the L-enantiomer (a-MLT) was active while the D-enantiomer (a-MDT) had negligible activity. The weight-loss effect was freely reversible, with the weight gain resuming soon after the withdrawal of the drug. All three models of obesity were associated with hyperglycemia, insulin resistance, and hepatic steatosis; a-MLT reversed these features. There was a decrease in food intake in the treatment group. Mice on a high-fat diet showed decreased cholesterol and protein in the serum when treated with a-MLT; there was however no evidence of liver and kidney dysfunction. Plasma amino acid profile indicated a significant decrease in the levels of specific amino acids, including tryptophan; but the levels of arginine were increased. We conclude that a-MLT is an effective, reversible, and orally active drug for the treatment of obesity and metabolic syndrome.

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