Therapeutic Ketosis Decreases Methacholine Hyperresponsiveness in Mouse Models of Inherent Obese Asthma

Obese asthmatics tend to have severe, poorly controlled disease and exhibit methacholine hyperresponsiveness manifesting in proximal airway narrowing and distal lung tissue collapsibility. Substantial weight loss in obese asthmatics or in mouse models of the condition decreases methacholine hyperresponsiveness. Ketone bodies are rapidly elevated during weight loss, coinciding with or preceding relief from asthma-related comorbidities. As ketone bodies may exert numerous potentially therapeutic effects, augmenting their systemic concentrations is being targeted for the treatment of several conditions. Circulating ketone body levels can be increased by feeding a ketogenic diet or by providing a ketone ester dietary supplement, which we hypothesized would exert protective effects in mouse models of inherent obese asthma. Weight loss induced by feeding a low-fat diet to mice previously fed a high-fat diet was preceded by increased urine and blood levels of the ketone body, β-hydroxybutyrate (BHB). Feeding a ketogenic diet for three weeks to high-fat diet-fed obese mice or genetically obese db/db mice increased BHB concentrations and decreased methacholine hyperresponsiveness without substantially decreasing body weight. Acute ketone ester administration decreased methacholine responsiveness of normal mice, and dietary ketone ester supplementation of high-fat diet-fed mice decreased methacholine hyperresponsiveness. Ketone ester supplementation also transiently induced an 'anti-obesogenic' gut microbiome with a decreased Fermicutes/Bacteroidetes ratio. Dietary interventions to increase systemic BHB concentrations could provide symptom relief for obese asthmatics without the need for the substantial weight loss required of patients to elicit benefits to their asthma through bariatric surgery or other diet or lifestyle alterations.

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Influence of a mineralocorticoid receptor blockade on vascular function in atherosclerotic mouse models under high-fat diet

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0034-1371981 ◽

2014 ◽

Vol 122 (03) ◽

Author(s):

C Brunssen ◽

J Rissler ◽

H Langbein ◽

A Hofmann ◽

A Deussen ◽

...

Keyword(s):

Mouse Models ◽

High Fat Diet ◽

Vascular Function ◽

Mineralocorticoid Receptor ◽

Receptor Blockade ◽

High Fat ◽

Mineralocorticoid Receptor Blockade

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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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Baicalin Attenuates High Fat Diet-Induced Obesity and Liver Dysfunction: Dose-Response and Potential Role of CaMKKβ/AMPK/ACC Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000374037 ◽

2015 ◽

Vol 35 (6) ◽

pp. 2349-2359 ◽

Cited By ~ 42

Author(s):

Youli Xi ◽

Miaozong Wu ◽

Hongxia Li ◽

Siqi Dong ◽

Erfei Luo ◽

...

Keyword(s):

Protein Kinase ◽

Fatty Liver ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Liver Steatosis ◽

Serum Levels ◽

Whole Body ◽

Therapeutic Effects ◽

High Fat ◽

Dependent Protein

Background/Aims: Obesity-associated fatty liver disease affects millions of individuals. This study aimed to evaluate the therapeutic effects of baicalin to treat obesity and fatty liver in high fat diet-induced obese mice, and to study the potential molecular mechanisms. Methods: High fat diet-induced obese animals were treated with different doses of baicalin (100, 200 and 400 mg/kg/d). Whole body, fat pad and liver were weighed. Hyperlipidemia, liver steatosis, liver function, and hepatic Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ) / AMP-activated protein kinase (AMPK) / acetyl-CoA carboxylase (ACC) were further evaluated. Results: Baicalin significantly decreased liver, epididymal fat and body weights in high fat diet-fed mice, which were associated with decreased serum levels of triglycerides, total cholesterol, LDL, alanine transaminase and aspartate transaminase, but increased serum HDL level. Pathological analysis revealed baicalin dose-dependently decreased the degree of hepatic steatosis, with predominantly diminished macrovesicular steatosis at lower dose but both macrovesicular and microvesicular steatoses at higher dose of baicalin. Baicalin dose-dependently inhibited hepatic CaMKKβ/AMPK/ACC pathway. Conclusion: These data suggest that baicalin up to 400 mg/kg/d is safe and able to decrease the degree of obesity and fatty liver diseases. Hepatic CaMKKβ/AMPK/ACC pathway may mediate the therapeutic effects of baicalin in high fat diet animal model.

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Contributions of a high-fat diet to Alzheimer's disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models

NeuroImage Clinical ◽

10.1016/j.nicl.2018.11.016 ◽

2019 ◽

Vol 21 ◽

pp. 101606 ◽

Cited By ~ 15

Author(s):

Colleen P.E. Rollins ◽

Daniel Gallino ◽

Vincent Kong ◽

Gülebru Ayranci ◽

Gabriel A. Devenyi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

High Fat Diet ◽

High Fat ◽

Structural Neuroimaging ◽

Neuroimaging Study

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Expression of eotaxin in 3T3-L1 adipocytes and the effects of weight loss in high-fat diet induced obese mice

Nutrition Research and Practice ◽

10.4162/nrp.2011.5.1.11 ◽

2011 ◽

Vol 5 (1) ◽

pp. 11 ◽

Cited By ~ 7

Author(s):

Hyun-Jung Kim ◽

Chang-Hyun Kim ◽

Do-Hyun Lee ◽

Min-Woo Han ◽

Mi-Young Kim ◽

...

Keyword(s):

Weight Loss ◽

High Fat Diet ◽

Obese Mice ◽

High Fat

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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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Abstract 686: Intervention with Naringenin Enhances Weight Loss, Potentiates Improvements in Metabolic Dysregulation and Halts Progression of Atherosclerosis Induced by a High-Fat Diet in LDLr-/- Mice.

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.686 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Amy C Burke ◽

Brian G Sutherland ◽

Julia M Assini ◽

Murray W Huff

Keyword(s):

Insulin Resistance ◽

Weight Loss ◽

Plasma Glucose ◽

High Fat Diet ◽

Lesion Size ◽

Chow Diet ◽

High Fat ◽

Metabolic Dysregulation ◽

The Metabolic Syndrome ◽

Progression Of Atherosclerosis

Previous studies demonstrate that the addition of naringenin, a grapefruit flavonoid, to a high-fat diet prevents the development of many disorders of the metabolic syndrome and atherosclerosis in Ldlr-/- mice. Furthermore, in intervention studies, the addition of naringenin to a high-fat, high cholesterol (HFHC) diet reversed pre-established obesity, hyperlipidemia, hepatic steatosis, insulin resistance and improved atherosclerotic lesion pathology, but not lesion size. In the present intervention study, we tested the hypothesis that addition of naringenin to a chow diet would further improve pre-established metabolic dysregulation and attenuate lesion development, compared to chow alone. Ldlr-/- mice were fed a HFHC diet for 12 weeks to induce metabolic dysregulation. Subsequently, mice received one of 3 diets for another 12 weeks: 1) continuation of the HFHC diet, 2) an isoflavone-free chow diet or 3) isoflavone-free chow with 3% naringenin. At 12 weeks, the HFHC diet induced significant weight gain and increased adiposity. Intervention with chow alone reduced the weight gained during induction by 22%, whereas the addition of naringenin to chow induced a weight loss of 71%. Specifically, the reduction in adiposity was 2.75-times greater in naringenin-treated mice, compared to chow alone. The HFHC diet increased VLDL cholesterol 20-fold and LDL cholesterol 5-fold, which were reduced by intervention with both chow (>60%) and chow supplemented with naringenin (>80%). The HFHC diet induced insulin resistance and glucose intolerance. Naringenin improved insulin tolerance (plasma glucose AUC -38%) and glucose tolerance (plasma glucose AUC -58%), which was accompanied by normalization of plasma insulin and glucose. HFHC-induction promoted the development of intermediate atherosclerotic lesions. Continuation of the HFHC diet doubled lesion size. Intervention with chow alone attenuated lesion size progression by 65%. The addition of naringenin to chow slowed lesion progression by 90%, resulting in smaller lesions compared to chow intervention alone (P=0.042). We conclude that intervention with naringenin-supplemented chow enhances weight loss, improves metabolic dysregulation and halts the progression of atherosclerosis.

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Modulation of Cognition: The Role of Gnidia glauca on Spatial Learning and Memory Retention in High-Fat Diet-Induced Obese Rats

Neural Plasticity ◽

10.1155/2019/2867058 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16

Author(s):

Wycliffe Makori Arika ◽

Cromwell Mwiti Kibiti ◽

Joan Murugi Njagi ◽

Mathew Piero Ngugi

Keyword(s):

Body Weight ◽

Learning And Memory ◽

Spatial Learning ◽

High Fat Diet ◽

Spatial Learning And Memory ◽

Therapeutic Effects ◽

Memory Retention ◽

High Fat ◽

Obesity Index ◽

Obese Rats

Chronic exposures to high-fat diets are linked to neuropathological changes that culminate in obesity-related cognitive dysfunction and brain alteration. Learning, memory performance, and executive function are the main domains affected by an obesogenic diet. There are limited effective therapies for addressing cognitive deficits. Thus, it is important to identify additional and alternative therapies. In African traditional medicine, Gnidia glauca has putative efficacy in the management of obesity and associated complications. The use of Gnidia glauca is largely based on its long-term traditional use. Its therapeutic application has not been accompanied by sufficient scientific evaluation to validate its use. Therefore, the current study sought to explore the modulatory effects of dichloromethane leaf extracts of Gnidia glauca on cognitive function in the high-fat diet- (HFD-) induced obese rats. Obesity was induced by feeding the rats with prepared HFD and water ad libitum for 6 weeks. The in vivo antiobesity effects were determined by oral administration of G. glauca at dosage levels of 200, 250, and 300 mg/kg body weight in HFD-induced obese rats from the 6th to the 12th weeks. The Lee obesity index was used as a diagnostic criterion of obesity. The Morris water maze was employed to test spatial learning and memory retention in rats. The results indicated that Gnidia glauca showed potent antiobesity effects as indicated in the reduction of body weight and obesity index in extract-treated rats. Moreover, Gnidia glauca exhibited cognitive-enhancing effects in obese rats. The positive influences on cognitive functions might be attributed to the extracts’ phytochemicals that have been suggested to confer protection against obesity-induced oxidative damage, reduction of central inflammation, and increased neurogenesis. The therapeutic effects observed suggest that Gnidia glauca might be an alternative to current medications for the symptomatic complications of obesity, such as learning and memory loss. Further studies are therefore needed to establish its toxicity profiles.

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