Obesity is becoming a growing concern in the global population, as more is learned about the negative health effects of obesity. Severe obesity, in which a person is 50 Kg or more over ideal body weight, in particular poses significant risks for severe health problems. Accordingly, a great deal of attention is being focused on treating obese patients.
Appetite suppressing pathways have been the focal point of anti-obesity drug development, since obesity is thought to be due to excess energy intake over energy expenditure. Limiting the caloric intake, however, induces compensatory adaptations that resist weight loss, Because nutrient-sensing neurons cross talk with cognitive and behavioural components, appetite suppressants tend to produce unacceptable psychiatric side effects. However, because of the complexity of the regulation of adipogenesis, few other pathways have been explored.
Diabetes is a metabolic disorder characterised by high blood glucose levels combined with relative insulin deficiency and insulin resistance. The majority of diabetic patients suffer from type 2 diabetes also known as late onset diabetes, and the incidence of this type of diabetes has spiralled in the last few years in line with an increase in obesity.
The function of BAT is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance, Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus.
BAT is abundant in rodents and human neonates but adult humans possess very little BAT and amounts decrease with aging. The amount of BAT in both rodents and humans is inversely correlated with obesity, such that rodents with defects in genes promoting BAT formation and function are prone to obesity and in humans greater amounts of BAT are observed in younger, leaner individuals than in older, overweight subjects. Therefore methods to activate BAT tissue in obese individuals or to increase BAT mass would be expected to have a positive effect on weight loss and susceptibility to obesity associated morbidities, Accordingly, a number of proposals have been made for the introduction of BAT into adult humans to combat obesity, For example, U.S. Pat. No. 6,645,229 notes that that “brown adipose tissue (BAT) plays a role in the regulation of energy expenditure and that stimulating BAT can result in patient slimming. BAT activation is regulated by the sympathetic nervous system and other physiological, e.g., hormonal and metabolic, influences. When activated, BAT removes free fatty acids (FFA) and oxygen from the blood supply for the generation of heat.” Neonatal BAT and adult human BAT appear to differ in certain characteristics. For example, neonatal or classical BAT is derived from a Myf5 expressing muscle-like cellular lineage. So-called beige or brite fat comes from a different lineage, from within white adipose tissue (WAT). Recently, it has been proposed that all adult human BAT is beige/brite, rather than classical BAT (Wu et al., 2012 Cell 150:1-11)
Activating or increasing BAT mass can also have a positive effect on diseases associated with BAT—in particular diabetes (Vegiopoulos et al, 2010, Science 328 (1158-61); Seale et al 2001, JCI 121 (96-105); Bostrom et al 2012 Nature 481 (463-68), In the simplest scenario BAT can improve type II diabetes by reducing obesity and therefore WAT depots, thus reducing their induction of insulin resistance. However BAT can also improve metabolic dysfunction beyond that expected by reduction in obesity alone. This is evidenced by the fact that increased BAT improved insulin sensitivity in overweight mice even when they didn't lose weight. It has been shown that BAT can also directly influence insulin secretion from islet cells in response to glucose, improving glucose homeostasis (Guerra et al, JCI, 2001,108 (1205-1213). in addition it has recently been shown that BAT transplants in mice robustly improve the metabolic condition of obese, insulin resistant mice (Liu, et al., (2013). Cell research, 1-4; Stanford, et al., (2013) The Journal of clinical investigation, 123(1), 215-223), and to restore normoglycemia and glucose tolerance in streptozotocin-induced diabetic mice (Gunawardana & Piston, 2012 Diabetes, 61(3), 674-82). In addition to acting as a glucose and energy sink, brown adipocytes are likely to also secrete factors (locally and/or in the circulation) that may have beneficial effects on glucose metabolism/insulin sensitivity and overall energy balance, like IL-6 (Stanford et al., 2013).
WO2009137613 describes a method for generating BAT, on the basis of the discovery that stem cell antigen-1 positive (Sca-1+) progenitor cells treated with one or more bone morphogenic proteins (BMP) differentiate to or towards BAT cells. These BAT cells are described as genuine BAT cells with a complete capacity to respond to catecholamine stimulation by turning on the BAT cell thermogenic program.
Nishio et al, Cell Metabolism 16:394,2012, describe the generation of BAT cells from human pluripotent stern cells, The BAT generated is of the classical, rather than brite, lineage.
More recently, WO2013/123214 described the generation of human BAT from artery-derived cells by exposing internal mammary artery-derived cells (iMACs) to an adipogenic instruction medium.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.