A comparison of a mouse unable to produce leptin thus resulting in<unk>  (left) and a normal mouse (right) Two distinct but related processes are considered to be involved in the development of<unk> : sustained positive energy balance (energy intake exceeding energy expenditure) and the resetting of the body weight "set point" at an increased value. The second process explains why finding effective<unk>  treatments has been difficult. While the underlying biology of this process still remains uncertain, research is beginning to clarify the mechanisms. At a biological level, there are many possible pathophysiological mechanisms involved in the development and maintenance of<unk> . This field of research had been almost unapproached until the leptin gene was discovered in 1994 by J. M. Friedman's laboratory. While leptin and ghrelin are produced peripherally, they control appetite through their actions on the central nervous system. In particular, they and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite, the melanocortin pathway being the most well understood. The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively. The arcuate nucleus contains two distinct groups of neurons. The first group coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of<unk> .
Obesity
Heart failure
Body mass index
Metabolic syndrome
Abdominal obesity
Family history 
Dry sex
Smoking