Obesity is now a deadly global pandemic. The prevalence of overweight plus obesity among adults in USA in 2008 was 68% (˜200 million people). Even a modest degree of obesity, particularly if the excess fat is located in the abdomen, increases the risks for type 2 diabetes mellitus, cardiovascular diseases, stroke and some forms of cancer. The economic cost of obesity is estimated to be $270 billion annually. Methods for managing body weight by dietary restriction and/or by exercise are largely ineffective as few people stick to dietary regimens for a long time, and compliance to regular exercise is equally poor. The result is generally a transient phase of weight loss (or weight stability) followed by a return on the trajectory towards obesity. These failures have highlighted the need for safe anti-obesity therapies.
In humans and many other mammals, fat is stored in adipose tissues. Adipose tissues are classified into two types-white adipose tissue (i.e., “white fat”) and brown adipose tissue (i.e., “brown fat”). White fat stores calories as large lipid droplets within individual cells.1 After food consumption, excess calories are stored as fat in white fat, which is mainly located under the skin of the buttocks and legs in women and around the internal organs in men. By contrast, brown fat stores little fat, instead burning it to produce heat and regulate body temperature.1 Brown fat's ability to burn rather than store calories depends on each brown fat cell having many mitochondria. The mitochondria of brown fat cells are unique in that they contain UCP1, a protein that uncouples metabolism from ATP production in order to produce heat.2 Small mammals and newborn humans have copious amounts of brown fat around their shoulder blades, which help them survive cold temperatures. Recent studies have conclusively identified brown fat in adult humans, mainly around the muscles of the lower neck and collarbone, as well as along the spine of the chest and abdomen.3-5 The concept of managing obesity through the stimulation of thermogenesis in brown fat is currently a focus of considerable attention by the pharmaceutical, nutraceutical and functional food industries.6 The skeletal muscle is another tissue involved in thermogenesis, and drugs that target thermogenesis by this tissue might also have value in the control of obesity.6,7 
Brown fat is mainly enervated by the sympathetic nervous system. When hormonally activated, brown fat generates heat and burns excess energy. In experimental animals, thermogenesis in brown fat is controlled by norepinephrine released from the sympathetic nervous system; norepinephrine interacts mainly with β-adrenergic receptors to stimulate thermogenesis (FIG. 1).2,8 Therefore, in rats, the β-adrenergic antagonist propranolol (5 mg/kg body wt) eliminates 18-fluoro-deoxyglucose uptake into brown fat.8,9. In man, propranolol (1 mg/kg) has the same effect10,11, clearly indicating that, also in man, glucose uptake (and thus probably thermogenesis) is under β-adrenergic control.
The idea of stimulating thermogenesis to manage or to assist in the management of obesity has a long history.6 Thyroid extracts utilized in obesity therapy at the end of the 19th century induced marked reductions in body weight, but their use in obesity therapy fell into disrepute because of unacceptable side effects, including cardiac stimulation and increased protein catabolism.6 Once the pivotal role of the sympatho-adrenal system in inducing thermogenesis in brown fat and skeletal muscle was understood, human trials in the 1990s evaluated all clinically-used sympathomimetic drugs for thermogenic anti-obesity properties.12 However, the pharmaceutical companies were concerned about developing old drugs, many off patent-protection, as anti-obesity drugs. Around this time, the b3-adrenoceptors was reported to be the key receptor via which sympathetically released NA activated thermogenesis and fat oxidation in peripheral tissues, including the activation of UCP1 that mediates thermogenesis in brown fat. In rodents and dogs, several b3-adrenoceptor agonists were shown to have potent thermogenic anti-obesity effects—without producing the cardiovascular side effects associated with classical adrenoceptor stimulation.13 The b3-adrenoceptors were demonstrated in human adipose tissue and skeletal muscle. However, these drugs either had poor selectivity for the human b3-adrenoceptor or poor oral availability, and no drug has progressed beyond phase II clinical trials.13 
Parallel efforts to promote thermogenesis for treatment of obesity and obesity-related disorders have included phytotherapy (e.g. Ma Huang and Guarana), and food ingredients (methylxanthines, polyphenolic compounds, capsaicinoids and capsinoids, high protein diets and diets rich in long-chain unsaturated fatty acids). In this regard, U.S. Pat. No. 6,451,336 (Sugano, et al.) entitled Agent for Increasing Brown Fat Comprising Conjugated Linoleic Acid as Active Ingredient describes methods for stimulating production of brown adipose tissue by administering conjugated linoleic acid. Also, U.S. Pat. No. 5,453,270 (Bills) describes methods for increasing the amount of brown adipose tissue in a subject by administering to the subject a quantity of cultured brown adipose cells encapsulated in a semi-permeable membrane.
Besides pharmaceutical or nutritional approaches, it may be possible to stimulate brown fat activity by exposure to colder climates. In a 2009 study published in The New England Journal of Medicine, entitled “Identification and Importance of Brown Adipose Tissue in Adult Humans”, the authors reported that brown fat activity decreased when the outdoor temperature was increased. Furthermore, a recent study in mice showed that short term exposure to cold accelerated plasma clearance of triglycerides as a result of increased uptake into brown fat, and in pathological conditions, cold exposure corrected hyperlipidemia.14 These findings could be useful because individuals with metabolically active brown fat may be able to lose weight by exposure to cold. Weight loss might also be achieved through drugs that mimic the cold by activating the sympathetic nervous system.
Another possible use could be to take advantage of the correlation between brown fat and the finding that the zinc-finger protein PRDM16 is highly enriched in brown fat cells compared to white fat cells. A 2007 study found that the transgenic expression of PRDM16 at physiological levels in white fat depots stimulates the formation of brown fat cells, while depletion of PRDM16 through shRNA expression in brown fat cells causes a near total loss of the brown characteristics.
Both voltage-gated potassium channels (IKv) and calcium-activated potassium channels (IKca) are present in the cell membranes of brown adipose tissue cells. See, Lucero, M. T. et al.; Voltage-Gated Potassium Channels in Brown Fat Cells; J. Gen. Physiol. 93: 451-472 (1989). However, in prior studies using the potassium channel blocker tetraethylammonium (TEA), it was concluded that blockade of potassium channels in brown fat does not alter the metabolic response of brown adipose tissue cells to adrenergic stimulation. Pappone, P A., et al., Potassium Channel Block Does Not Affect Metabolic Responses of Brown Fat Cells; Am J Physiol. 262(3 Pt 1):C678-81 (1992).
Accordingly, there exists a need for the development of agents and methods to stimulate generation and activation of brown adipose tissue and/or skeletal muscle to promote weight loss and increase insulin sensitivity.    1. Stephen R. Farmer. Be cool, lose weight. Nature 458, 839-840, 2009    2. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277-359, 2004.    3. Virtanen, K. A. et al. N. Eng. J. Med. 360, 1518-1525, 2009.    4. van Marken Lichtenbelt, W. D. et al. N. Eng. J. Med. 360, 1500-1508, 2009.    5. Cypess, A. M. et al. N. Eng. J. Med. 360, 1509-1517, 2009.    6. Dulloo A G. The search for compounds that stimulate thermogenesis in obesity management: from pharmaceuticals to functional food ingredients. Obes. Rev. 12:866-883, 2011    7. Clapham J C et al. Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406:415-418,2000    8. Jan Nedergaard, Tore Bengtsson, and Barbara Cannon. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293:E444-E452, 2007.    9. Tatsumi M, Engles J M, Ishimori T, Nicely O, Cohade C, Wahl R L. Intense (18)F-FDG uptake in brown fat can be reduced pharmacologically. J Nucl Med 45:1189-1193, 2004    10. Jacobsson H, Bruzelius M, Larsson S A. Reduction of FDG uptake in brown adipose tissue by propranolol. Eur J Nucl Med Mol Imaging 32: 1130, 2005.    11. Soderlund V, Larsson S A, Jacobsson H. Reduction of FGD uptake in brown adipose tissue in clinical patients by a single dose of propranolol. Eur J Nucl Med Mol Imaging. 34:1018-22, 2007.    12. Dulloo A G, Seydoux J, Girardier L. Dietary and pharmacological effectiveness of thermogenic stimulation in obesity treatment. In: Oomura Y, Tarui S, Inoue S, Shimazu T (eds). Progress in Obesity Research 1990. John Libbey & Company Ltd: London, 1990, pp. 135-144.    13. Arch J R. The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from beta3-adrenoceptor agonists. Naunyn Schmiedebergs Arch Pharmacol; 378: 225-240, 2008.    14. Bartell A. et al., Brown adipose tissue activity controls triglyceride clearance. Nature Medicine 17:200-5, 2011