Leptin is a major hormone regulator of fat mass in vertebrates. It's a frequent topic on this blog because I believe it's central to overweight and modern metabolic disorders. Here's how it works. Leptin is secreted by fat tissue, and its blood levels are proportional to fat mass. The more fat tissue, the more leptin. Leptin reduces appetite, increases fat release from fat tissue and increases the metabolic rate. Normally, this creates a "feedback loop" that keeps fat mass within a fairly narrow range. Any increase in fat tissue causes an increase in leptin, which burns fat tissue at an accelerated rate. This continues until fat mass has decreased enough to return leptin to its original level.
Leptin was first identified through research on the "obese" mutant mouse. The obese strain arose by a spontaneous mutation, and is extremely fat. The mutation turned out to be in a protein investigators dubbed leptin. When researchers first discovered leptin, they speculated that it could be the "obesity gene", and supplemental leptin a potential treatment for obesity. They later discovered (to their great chagrin) that obese people produce much more leptin than thin people, so a defeciency of leptin was clearly not the problem, as it was in the obese mouse. They subsequently found that obese people scarcely respond to injected leptin by reducing their food intake, as thin people do. They are leptin resistant. This makes sense if you think about it. The only way a person can gain significant fat mass is if the leptin feedback loop isn't working correctly.
Another rodent model of leptin resistance arose later, the "Zucker fatty" rat. Zucker rats have a mutation in the leptin receptor gene. They secrete leptin just fine, but they don't respond to it because they have no functional receptor. This makes them an excellent model of complete leptin resistance. What happens to Zucker rats? They become obese, hypometabolic, hyperphagic, hypertensive, insulin resistant, and they develop blood lipid disturbances. It should sound familiar; it's the metabolic syndrome and it affects 24% of Americans (CDC NHANES III). Guess what's the first symptom of impending metabolic syndrome in humans, even before insulin resistance and obesity? Leptin resistance. This makes leptin an excellent contender for the keystone position in overweight and other metabolic disorders.
I've mentioned before that the two most commonly used animal models of the metabolic syndrome are both sugar-fed rats. Fructose, which accounts for 50% of table sugar and 55% of high-fructose corn syrup, is probably the culprit. Glucose, which is the remainder of table sugar and high-fructose corn syrup, and the product of starch digestion, does not have the same effects. I think it's also relevant that refined sugar contains no vitamins or minerals whatsoever. Sweetener consumption in the U.S. has increased from virtually nothing in 1850, to 84 pounds per year in 1909, to 119 pounds in 1970, to 142 pounds in 2005 (source).
In a recent paper, Dr. Philip Scarpace's group (in collaboration with Dr. Richard Johnson), showed that a high-fructose diet causes leptin resistance in rats. The diet was 60% fructose, which is extreme by any standards, but it caused a complete resistance to the effect of leptin on food intake. Normally, leptin binds receptors in a brain region called the hypothalamus, which is responsible for food intake behaviors (including in humans). This accounts for leptin's ability to reduce food consumption. Fructose-fed rats did not reduce their food intake at all when injected with leptin, while rats on a normal diet did. When subsequently put on a high-fat diet (60% lard), rats that started off on the fructose diet gained more weight.
I think it's worth mentionong that rodents don't respond to high-fat diets in the same way as humans, as judged by the efficacy of low-carbohydrate diets for weight loss. Industrial lard also has a very poor ratio of omega-6 to omega-3 fats (especially if it's hydrogenated), which may also contribute to the observed weight gain.
Fructose-fed rats had higher cholesterol and twice the triglycerides of control-fed rats. Fructose increases triglycerides because it goes straight to the liver, which makes it into fat that's subsequently exported into the bloodstream. Elevated triglycerides impair leptin transport from the blood to the hypothalamus across the blood-brain barrier, which separates the central nervous system from the rest of the body. Fructose also impaired the response of the hypothalamus to the leptin that did reach it. Both effects may contribute to the leptin resistance Dr. Scarpace's group observed.
Just four weeks of fructose feeding in humans (1.5g per kg body weight) increased leptin levels by 48%. Body weight did not change during the study, indicating that more leptin was required to maintain the same level of fat mass. This may be the beginning of leptin resistance.