scholarly journals Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity

2019 ◽  
Author(s):  
Belén Palomares ◽  
Francisco Ruiz-Pino ◽  
Martin Garrido-Rodriguez ◽  
M. Eugenia Prados ◽  
Miguel A. Sánchez-Garrido ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Fat Mass ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Liver Steatosis ◽  
High Fat ◽  
Present Evidence ◽  
Pparγ Agonist ◽  
Psychotropic Effects

ABSTRACTCannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ9-THC (Δ9-THC acid A, Δ9-THCA-A) is still largely unexplored. We present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and with an enhanced osteoblastogenic activity in human mesenchymal stem cells. Docking andin vitrofunctional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures at inguinal white adipose tissue (iWAT) from mice treated with Δ9-THCA-A confirmed its mode of action on PPARγ. Administration of Δ9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Altogether, our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation. These findings suggest that Δ9-THCA-A, and perhaps non-decarboxylatedCannabis sativaextracts, are worth considering for addition to our inventory of cannabis medicines.SIGNIFICANCE STATEMENTThe medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of Δ9-THC, the decarboxylation product of its naturally occurring and non-psychotropic precursor Δ9-THCA-A. We present evidence that Δ9-THCA-A is a partial ligand agonist of PPARγ with lower adipogenic activity compared to the full PPARγ agonist rosiglitazone (RGZ). Moreover, chronic administration of Δ9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced body weight gain and fat mass, improved glucose intolerance and insulin resistance, and prevented liver steatosis and macrophage infiltration in fat tissues, additionally inducing white adipose tissue browning. Collectively, these observations qualify Δ9-THCA-A, a compound devoid of psychotropic effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesity-associated inflammation.Highlights- Δ9-THCA-A is a partial PPARγ ligand agonist with low adipogenic activity- Δ9-THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.- Δ9-THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice- Δ9-THCA-A improves glucose tolerance, insulin sensitivity, and insulin profilesin vivo- Δ9-THCA-A induces browning of iWAT and has a potent anti-inflammatory activity

scholarly journals Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

2016 ◽  
Vol 48 (7) ◽  
pp. 491-501 ◽  
Author(s):  
Madeliene Stump ◽  
Deng-Fu Guo ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Energy Balance ◽  
High Fat Diet ◽  
Control Diet ◽  
Cre Recombinase ◽  
Dominant Negative ◽  
High Fat ◽  
Pparγ Agonist ◽  
The Brain

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ-P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

scholarly journals Tetrahydro iso-Alpha Acids from Hops Improve Glucose Homeostasis and Reduce Body Weight Gain and Metabolic Endotoxemia in High-Fat Diet-Fed Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e33858 ◽  
Author(s):  
Amandine Everard ◽  
Lucie Geurts ◽  
Marie Van Roye ◽  
Nathalie M. Delzenne ◽  
Patrice D. Cani
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
High Fat ◽  
Reduce Body Weight ◽  
Metabolic Endotoxemia

scholarly journals Antiobesity Effect of a Novel Herbal Formulation LI85008F in High-Fat Diet-Induced Obese Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Hak Joo Choi ◽  
Hwa Young Kim ◽  
Kyoung Sik Park
Keyword(s):  
Weight Gain ◽  
Body Fat ◽  
Fat Mass ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Whole Body ◽  
Body Fat Mass ◽  
Obese Mice ◽  
High Fat ◽  
Herbal Formulation

A variety of natural products have been explored for their antiobesity potential and widely used to develop dietary supplements for the prevention of weight gain from excess body fat. In an attempt to find a natural antiobesity agent, this study was designed to evaluate the antiobesity activity of a novel herbal formulation LI85008F composed of extracts from three medicinal plants in high-fat diet- (HFD-) induced obese mice. After the thirteen-week oral administration of the test materials to mice, the body weight gain, whole-body fat mass, adipose tissue weight, and the expression levels of obesity-related proteins were measured. Our results indicated that LI85008F can suppress body weight gain and lower whole-body fat mass in HFD-induced obese mice. Significant decreases in epididymal and retroperitoneal fat mass were observed in LI85008F-treated groups compared with the HFD-fed control group ( p < 0.05 ). Furthermore, the oral administration of LI85008F caused significant decreases in the expression level of adipogenic (C/EBPα and PPARγ) and lipogenic (ACC) markers and notable increases in the production level of thermogenetic (AMPKα, PGC1α and UCP1) and lipolytic (HSL) proteins. These findings suggest that LI85008F holds great promise for a novel herbal formulation with antiobesity activities, preventing body fat accumulation and altering lipid metabolism.

scholarly journals Fish oil suppresses obesity more potently in lean mice than in diet-induced obese mice but ameliorates steatosis in such obese mice

2021 ◽  
Vol 85 (2) ◽  
pp. 421-429
Author(s):  
Sachiko Okue ◽  
Eimi Ishikawa ◽  
Ren Nakahara ◽  
Tsubasa Ito ◽  
Takumi Okura ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Fish Oil ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Liver Steatosis ◽  
Obese Mice ◽  
Food Efficiency ◽  
Lard Diet

ABSTRACT This study sought to clarify the antiobesity effects of fish oil (FO) in terms of prevention and amelioration. An isocaloric diet composed of lard or FO was given to lean C57BL/6J mice for the study of prevention and high-fat diet-induced obese (DIO) mice for the study of amelioration for 4 weeks. Body weight gain and food efficiency were potently suppressed by FO in lean mice compared to lard diet-fed mice. Uncoupling protein-1 (UCP-1) expression in inguinal white adipose tissue (WAT) was also significantly induced by FO in lean mice. FO also suppressed body weight gain and food efficiency in DIO mice but did not reduce body weight. FO ameliorated liver steatosis in DIO mice by mildly inducing UCP-1 in inguinal WAT. FO suppressed obesity more potently in lean mice than in DIO mice but ameliorated steatosis in the DIO mice.

scholarly journals High-fat and low-fat (behavioural) phenotypes: biology or environment?

1999 ◽  
Vol 58 (4) ◽  
pp. 773-777 ◽  
Author(s):  
John E. Blundell ◽  
John Cooling
Keyword(s):  
Risk Factors ◽  
Body Weight ◽  
Risk Factor ◽  
Weight Gain ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Positive Energy ◽  
High Fat ◽  
Low Fat ◽  
Conceptual Tool

It is now widely accepted that obesity develops by way of genetic mechanisms conferring specific dispositions which interact with strong environmental pressures. It is also accepted that certain dispositions constitute metabolic risk factors for weight gain. It is less well accepted that certain patterns of behaviour (arising from biological demands or environmental influences) put individuals at risk of developing a positive energy balance and weight gain (behavioural risk factors). Relevant patterns of behaviour include long-lasting habits for selecting and eating particular types of foods. Such habits define two distinct groups characterized as high-fat (HF) and low-fat (LF) phenotypes. These habits are important because of the attention given to dietary macronutrients in body-weight gain and the worldwide epidemic of obesity. Considerable evidence indicates that the total amount of dietary fat consumed remains the most potent food-related risk factor for weight gain. However, although habitual intake of a high-fat diet is a behavioural risk factor for obesity, it does not constitute a biological inevitability. A habitual low-fat diet does seem to protect against the development of obesity, but a high-fat diet does not guarantee that an individual will be obese. Although obesity is much more prevalent among HF than LF, some HF are lean with BMI well within the normal range. The concept of 'different routes to obesity' through a variety of nutritional scenarios can be envisaged, with predisposed individuals varying in their susceptibility to different dietary inputs. In a particular subgroup of individuals (young adult males) HF and LF displayed quite different profiles of appetite control, response to nutrient challenges and physiological measures, including BMR, RQ, heart rate, plasma leptin levels and thermogenic responses to fat and carbohydrate meals. These striking differences suggest that HF and LF can be used as a conceptual tool to investigate the relationship between biology and the environment (diet) in the control of body weight.

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