Obesity is a disease with strongly increasing prevalence, and has reached epidemic proportions in the industrialized world. This disease is essentially characterized by an unbalance between energy intake and expenditure, which, without interference, leads to an endless increase in adipose tissue mass and body weight.
Appetite and energy intake are influenced by several hormonal effectors and neurotransmitters acting in the peripheral as well as the central nervous system. Examples of neurotransmitters acting to increase appetite and, concomitantly, body weight, are neuropeptide Y, melanin concentrating hormone, galanin, as well as glucocorticoid hormones. Examples of hormones or neurotransmitters that counteract feeding and stimulate reduction in adipose mass are melanocortin, corticotropin releasing factor, as well as the recently described peptide hormone leptin.
Brown adipose tissue (BAT) is a well characterized tissue which is well developed in newborn mammals, including man. One important task of BAT is to generate heat and maintain body temperature homeostasis in newborns, as well as in small animals, e.g. rodents.
The uncoupling protein, UCP-1, occurs in mitochondria, and seems to be the most important protein for generating heat in BAT. It does so by burning calories using a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in BAT during fuel oxidation. The fuel oxidation process is uncoupled for oxidative phosphorylation of ADP to ATP, thus generating heat which is distributed from BAT to the rest of the body via the circulation. The physiological external stimulus for uncoupling activity in BAT is cold temperature. This will increase the sympathetic nervous system activity and release of catecholamines leading to stimulation of beta3 adrenoreceptors present on the surface of brown adipocytes.
Recently, a new protein denoted UCP-2 has been discovered, which is expressed not only in BAT, but also in white adipose tissue (WAT), skeletal muscle, lung, heart, placenta, etc. (Fleury C, et al. (1997) "Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia" Nat Genet 15(3), 269-272; Gimeno, R E., et al., (1997) "Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis" Diabetes 46(5), 900-906). The UCP-2 protein has a 59% identity to UCP-1, and is upregulated in WAT in mice in response to feeding. This is in contrast to UCP-1, which is physiologically upregulated by cold in mice.
International patent document WO 9616031, to The Upjohn Company, discloses aminoguanidine carboxylates, e.g. [1-(hydrazinoiminomethyl)hydrazino]acetic acid for the treatment of non-insulin dependent diabetes mellitus. The novel and claimed compounds reduce the abnormally elevated blood glucose level and have an increased glucose tolerance.
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