Thermogenic and metabolic antiobesity drugs: rationale and opportunities

  title={Thermogenic and metabolic antiobesity drugs: rationale and opportunities},
  author={John C. Clapham and Jonathan Robert Sanders Arch},
Antiobesity drugs that target peripheral metabolism may avoid some of the problems that have been encountered with centrally acting anorectic drugs. Moreover, if they cause weight loss by increasing fat oxidation, they not only address a cause of obesity but also should promote loss of fat rather than lean tissue and improve insulin sensitivity. Weight loss may be slow but more sustained than with anorectic drugs, and thermogenesis may be insufficient to cause any discomfort. Some thermogenic… 

Detection of thermogenesis in rodents in response to anti-obesity drugs and genetic modification

Many compounds and genetic manipulations are claimed to confer resistance to obesity in rodents by raising energy expenditure, but it is demonstrated that such claims are often based on measurements of energy expenditure after body composition has changed, and depend on comparisons of energy Expenditure divided by body weight.

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

A comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism is provided.

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

This review article has 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.

The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β3-adrenoceptor agonists

  • J. Arch
  • Biology, Medicine
    Naunyn-Schmiedeberg's Archives of Pharmacology
  • 2008
Although β3-adrenoceptor (β3AR) agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery, the physiology of energy expenditure and

Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity

Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.

Responses of brown adipose tissue to diet-induced obesity, exercise, dietary restriction and ephedrine treatment.

  • Nikki SlocumJ. Durrant C. Elangbam
  • Medicine, Biology
    Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie
  • 2013

Stearoyl-CoA desaturase: a vital checkpoint in the development and progression of obesity.

The role of SCD-1 as a homeostatic check-point between glucose and fatty acid metabolism in the development and progression of obesity is evaluated and its prospects as a potential drug target for the management of obesity and related disorders are explored.

Myocyte Androgen Receptor Modulates Body Composition and Metabolic Parameters

It is shown that selective overexpression of AR in muscle cells of transgenic (HSA-AR) rodents both increases lean muscle mass and significantly reduces fat mass in males and in females treated with testosterone.



Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver, and suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1.

Prevention of diet-induced obesity with concomitant reductions in SCD1 expression and the ratio of oleate to stearoyl-CoA in tissues and plasma and pharmacological inhibition ofSCD1 represents a new target for the treatment of obesity and related metabolic disorders.

Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis*

These studies demonstrate the involvement of PPARα nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity in rodents.

Role of hypothalamic 5′-AMP-activated protein kinase in the regulation of food intake and energy homeostasis

Hypothalamic AMPK is an important signaling molecule that integrates nutritional and hormonal signals and modulates feeding behavior and energy metabolism, and appears to play a role in the central regulation of energy expenditure and peripheral glucose metabolism.

Acetyl-CoA carboxylase inhibition for the treatment of metabolic syndrome.

  • H. J. Harwood
  • Biology, Medicine
    Current opinion in investigational drugs
  • 2004
The heterogeneity of the patient population and the absence of established guidelines regarding approval endpoints for agents simultaneously affecting multiple aspects of metabolic syndrome will pose developmental challenges for initial market entries.

11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice

These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.

C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity

C75 acts both centrally to reduce food intake and peripherally to increase fatty acid oxidation, leading to rapid and profound weight loss, loss of adipose mass, and resolution of fatty liver, in mice and cellular models.

Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome.

Evidence is provided that long-term administration of AICAR improves glucose tolerance, improves the lipid profile, and reduces systolic blood pressure in an insulin-resistant animal model and gives additional support to the hypothesis that AMPK activation might be a potential future pharmacological strategy for treating the insulin resistance syndrome.

Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice.

Findings suggest that pharmacological inhibition of DGAT1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes.