BROWN ADIPOSE TISSUE, Β3-Adrenergic RECEPTORS, AND OBESITY

Bb, Lowell; Js, Flier

doi:10.1146/annurev.med.48.1.307

Cited by 215 publications

(37 citation statements)

References 70 publications

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“…This is consistent with the reported effects of CL316,243 on overall energy expenditure in BAT [33]. CL316,243 promotes BAT mitochondrial proliferation and energy expenditure in brown fat is capable of ranging over many orders of magnitude, controlled primarily by sympathetic stimulation mediated by rapid changes in UCP1 intrinsic activity [47]. In initial human studies with CL316,243 energy expenditure after 8 weeks in young lean males did not differ from baseline [48].…”

Section: Drug-induced Bat Activationsupporting

confidence: 83%

Classification of Therapeutic and Experimental Drugs for Brown Adipose Tissue Activation: Potential Treatment Strategies for Diabetes and Obesity

Baranwal¹,

Schade²

2016

CDR

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Objective: Increasing efforts are being made towards pharmacologic activation of brown adipose tissue (BAT) in animals and humans for potential use in the treatment of obesity and diabetes. We and others have reported a number of animal studies using either experimental or therapeutic drugs. There are now efforts to translate these findings to human studies. The goal of this review is to evaluate the various drugs currently being used that have the potential for BAT activation.Methods: Drugs were classified into 4 classes based on their mechanism of action. Class 1 drugs include the use of β3 adrenoceptor agonists for BAT activation. Class 2 drugs include drugs that affect norepinephrine levels and activate BAT with the potential of reducing obesity. Class 3 includes activators of peroxisome proliferator-activated receptor-γ in pursuit of lowering blood sugar, weight loss and diabetes and finally Class 4 includes natural products and other emerging drugs with limited information on BAT activation and their effects on diabetes and weight loss.Results: Class 1 drugs are high BAT activators followed by Class 2 and 3. Some of these drugs have now been extended to diabetes and obesity animal models and human BAT studies. Drugs in Class 3 are used clinically for Type 2 diabetes, but the extent of BAT involvement is unclear.Conclusion: Further studies on the efficacy of these drugs in diabetes and measuring their effects on BAT activation using noninvasive imaging will help in establishing a clinical role of BAT.

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Section: Drug-induced Bat Activationsupporting

confidence: 83%

Classification of Therapeutic and Experimental Drugs for Brown Adipose Tissue Activation: Potential Treatment Strategies for Diabetes and Obesity

Baranwal¹,

Schade²

2016

CDR

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“…The gene encoding the β3-adrenergic receptor, ADRB3 , was also more highly expressed after treatment (Figure 2d). Reduced expression of ADRB3 is frequently observed in obesity-associated catecholamine resistance (Collins et al, 1999; Lowell and Flier, 1997). We also observed increased expression of FGF21, a gene associated with the development and activation of beige fat (Owen et al, 2015) (Figure 2e).…”

Section: Amlexanox Improves Metabolic Parameters In An Open Label CLImentioning

confidence: 99%

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes

et al. 2017

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Summary Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKε and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKε/TBK1, in a proof-of-concept randomized, double blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that IKKε/TBK1 inhibitors may be effective therapies for metabolic disease in an identifiable subset of patients.

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“…Brown fat, which expresses relatively high levels of UCP1, is an exciting target for therapy. Despite the low amounts of brown fat in humans, as little as 50 g of brown fat has been estimated to be capable of utilizing up to 20% of basal caloric needs [52]; and mice with genetically reduced brown adipose tissue (BAT) mass are prone to obesity [53]. The recent discovery that adult humans maintain active depots of BAT [54, 55], in conjunction with the identification of UCP-2 and UCP-3 in the skeletal muscle and other tissues [56, 57], suggests that enhancement of mitochondrial activity may hold promise for combatting obesity.…”

Section: Metabolic Pathways Known To Regulate Obesitymentioning

confidence: 99%

Regulation of obesity and insulin resistance by nitric oxide

Sansbury

Hill

2014

Free Radical Biology and Medicine

220

193

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Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a world-wide pandemic with few tangible and safe treatment options. While it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many “distal” causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity—those that directly regulate energy metabolism or caloric intake—appear to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.

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BROWN ADIPOSE TISSUE, Β3-Adrenergic RECEPTORS, AND OBESITY

Cited by 215 publications

References 70 publications

Classification of Therapeutic and Experimental Drugs for Brown Adipose Tissue Activation: Potential Treatment Strategies for Diabetes and Obesity

Classification of Therapeutic and Experimental Drugs for Brown Adipose Tissue Activation: Potential Treatment Strategies for Diabetes and Obesity

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes

Regulation of obesity and insulin resistance by nitric oxide

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