Small molecules for fat combustion: targeting obesity

Ge, Chenchen; Wang, Ying; Lin, Ligen

doi:10.1016/j.apsb.2018.09.007

Cited by 88 publications

(55 citation statements)

References 152 publications

(199 reference statements)

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“…Obesity, type 2 diabetes and non-alcohol fatty liver disease are aspects of metabolic syndrome, which is a major public health problem worldwide36., 37., 38., 39., 40.. Thermogenesis is considered a therapeutic target for obesity 41 . The progress of metabolic syndrome results from interactions between the gut microbiota and the host 42 .…”

Section: Discussionmentioning

confidence: 99%

Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters

Sun

Pang

Wang

et al. 2019

Acta Pharmaceutica Sinica B

136

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Since metabolic process differs between humans and mice, studies were performed in hamsters, which are generally considered to be a more appropriate animal model for studies of obesity-related metabolic disorders. The modulation of gut microbiota, bile acids and the farnesoid X receptor (FXR) axis is correlated with obesity-induced insulin resistance and hepatic steatosis in mice. However, the interactions among the gut microbiota, bile acids and FXR in metabolic disorders remained largely unexplored in hamsters. In the current study, hamsters fed a 60% high-fat diet (HFD) were administered vehicle or an antibiotic cocktail by gavage twice a week for four weeks. Antibiotic treatment alleviated HFD-induced glucose intolerance, hepatic steatosis and inflammation accompanied with decreased hepatic lipogenesis and elevated thermogenesis in subcutaneous white adipose tissue (sWAT). In the livers of antibiotic-treated hamsters, cytochrome P450 family 7 subfamily B member 1 (CYP7B1) in the alternative bile acid synthesis pathway was upregulated, contributing to a more hydrophilic bile acid profile with increased tauro- β -muricholic acid (T β MCA). The intestinal FXR signaling was suppressed but remained unchanged in the liver. This study is of potential translational significance in determining the role of gut microbiota-mediated bile acid metabolism in modulating diet-induced glucose intolerance and hepatic steatosis in the hamster.

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Section: Discussionmentioning

confidence: 99%

Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters

Sun

Pang

Wang

et al. 2019

Acta Pharmaceutica Sinica B

136

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“…In fact, while initial strategies to tackle obesity were mostly focused in the control of food intake, growing interest has been paid recently to elucidate the physiological roles and eventual therapeutic use of adaptive thermogenesis in the control of body weight and energy homeostasis (21,22). Studies in this area have been directed not only to the brown adipose 115 tissue (BAT), where canonical adaptive thermogenesis occurs in mammals, including humans (23), but also to the capacity of the white adipose tissue (WAT) to undergo, under certain conditions, browning, a process whereby adipocyte precursor cells acquire brown-like features, becoming beige or brite adipocytes (24).…”

Section: Introduction 75mentioning

confidence: 99%

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

Palomares

Ruíz-Pino

Garrido‐Rodríguez

et al. 2019

Preprint

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25Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ 9 -tetrahydrocannabinol (Δ 9 -THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ 9 -THC (Δ 9 -THC acid A, Δ 9 -THCA-A) is still largely unexplored. We present evidence that Δ 9 -THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone 30 (RGZ) and with an enhanced osteoblastogenic activity in human mesenchymal stem cells.Docking and in vitro functional assays indicated that Δ 9 -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 Δ 9 -THCA-A confirmed its mode of action on PPARγ. Administration of Δ 9 -THCA-A in a mouse 35 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 Δ 9 -THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions 40 in HFD mice. Altogether, our data validate the potential of Δ 9 -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 Δ 9 -THCA-A, and perhaps non-decarboxylated Cannabis sativa extracts, are worth considering for addition to our inventory of cannabis medicines. 45Key words: Medicinal cannabis, Δ 9 -THCA-A, PPARγ, obesity, metabolic syndrome, inflammation 50 3 SIGNIFICANCE STATEMENTThe medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of Δ 9 -THC, the decarboxylation product of its naturally occurring and nonpsychotropic precursor Δ 9 -THCA-A. We present evidence that Δ 9 -THCA-A is a partial ligand agonist of PPARγ with lower adipogenic activity compared to the full PPARγ agonist 55 rosiglitazone (RGZ). Moreover, chronic administration of Δ 9 -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 Δ 9 -THCA-A, a compound devoid of psychotropic 60 effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesityassociated inflammation. 65Highlights -Δ 9 -THCA-A is a partial PPARγ ligand agonist with low adipogenic activity -Δ 9 -THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.-Δ 9 -THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice 70 -Δ 9 -THCA-A impro...

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“…Since the brown adipose tissue (BAT) shows substantial capacity to expedite energy, targeting brown adipogenic thermogenesis may be considered as a suitable therapeutic approach for the treatment or prevention of obesity and its associated disorders. Three review articles have discussed the potential and the application of thermogenesis in obesity and diabetes 3 – 5 .…”

Section: Therapeutic Strategy Based On Fat Combustion and Clinical Dementioning

confidence: 99%

Clinical Application Potential of Small Molecules that Induce Brown Adipose Tissue Thermogenesis by Improving Fat Metabolism

Dass

Tsai

et al. 2020

Cell Transplant

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Mammalian fat comprises white and brown adipose tissue (WAT and BAT, respectively). WAT stores energy, whereas BAT is used for thermogenesis. In recent years, the incidence of obesity and its associated disorders have increased tremendously. Considering the thermogenic capacity and decreased levels of BAT with increasing age, BAT can be used as a suitable therapeutic target for the treatment of obesity and diabetes. In several studies, using positron emission tomography and computed tomography images, adult humans have been shown to have functional BAT in interscapular fat. Results of these basic research studies on BAT have shed light on the new components of transcriptional regulation and the role of hormones in stimulating BAT growth and differentiation. In this review article, we have summarized the thermogenic regulators identified in the past decades by focusing on peroxisome proliferator-activated receptor gamma/uncoupling protein 1 activators, branched-chain amino acids, fatty acids (lipokine), and adenosine monophosphate-activated protein kinase mediators. We have also presented the progress of a few ongoing clinical trials aimed at the treatment of obesity and its associated metabolic disorders. The main purpose of this review was to provide a comprehensive introduction to the latest knowledge of the representative thermogenic regulators for the treatment of obesity. The fat combustion capacity of BAT may have great potential and can be considered as a suitable target for the therapeutic application of drugs from bench-to-bed treatment of obesity and the associated diseases.

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Small molecules for fat combustion: targeting obesity

Cited by 88 publications

References 152 publications

Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters

Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters

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

Clinical Application Potential of Small Molecules that Induce Brown Adipose Tissue Thermogenesis by Improving Fat Metabolism

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