This section will deal with the basic physiology of leptin -- particularly its expression and signaling. It will be fairly technical and perhaps not be the most satisfying of sections as far as real world information, but it will provide the background necessary for most fully understanding the sections to follow, as well as understanding any future data that becomes available -- so I suggest you read it carefully, nonetheless.
And, it probably would not be a bad idea to read it again after that.
Structure
Leptin is a 167 amino acid, 16 kDalton protein, which belongs, structurally, to the cytokine family (1), which includes interleukin-2, interleukin-12, and growth hormone. The former characteristics have some important implications for any exogenous administration. Like other proteins such as insulin and growth hormone, it would not pass through the GI intact, thus oral use is out of the question. It is also far too large for transdermal administration.
All of this is a moot point, anyway, as it costs about $1000 a day at this point.
Recently, scientists have also been looking at various other ligands based upon partial amino acid sequences of the leptin protein (2), and a few have been found effective. While they would still not be candidates for oral or transdermal delivery, intranasal (as well as rectal and vaginal) delivery might be an option.
Leptin Expression
It appears that leptin is not stored in any significant quantities. No large storage organelles for leptin have been found in adipocytes (3). And, studies looking at the kinetics of leptin synthesis and secretion in response to known secretagogues found no evidence of leptin release from stored cytosolic pools (4). Thus, and increases in leptin release are due to an increase in leptin expression.
Leptin is synthesized primarily in adipose tissue, with minor contribution coming from gastric mucosa, skeletal muscle (5), and possibly the brain (6). In mice, mutations of the ob gene (and subsequent lack of leptin production) cause hyperphagia and early and rapid onset of obesity. However, this mutation is quite rare in humans (7).
Numerous factors alter leptin synthesis and secretion including genetics, various nutrients, sex hormones, insulin, catecholamines, fat free mass, fat stores, and energy balance (5, 8, 9). Within an individual, the two most important factors are fat stores and energy balance.
Adipose Stores
Leptin acts, in the long-term, as a signaller of energy stores. It is primarily energy stored in adipose tissue that is responsible for this signal, though fat free mass has been found in one study to contribute to leptin expression (10). Though, the exact mechanisms of the signal are not yet known, increases in both fat cell size (11, 12) and fat cell number (13) have been associated with increases in leptin levels, with size perhaps being more important in women and number more important in men (13).
Subjects in the highest 5% of bodyfat have leptin levels of 40.4ng/ml for women and 15.6 for men vs. 3.3 and 1.5, respectively, for the lowest 5% (14). The significance of these numbers will become more clear as you read on.
Energy Balance
In the short-term, leptin is primarily regulated by energy balance, with a negative balance -- either through fasting/dieting or exercise -- causing a fall in leptin levels, while a positive energy balance causes a rise in leptin levels (5, 8).
Three days of fasting in lean females caused a 62% fall in leptin levels. In the same study, a 700 calorie/day diet in obese men resulted in a 76% decrease in leptin levels, despite only a 21% weight loss over three months (15). In another study, a two and a half day fast resulted in a 78% drop (16).