The proximal cause of obesity is, of course, the organism storing energy substrate as fat, in subcutaneous and visceral adipocytes and ectopically on muscle, rather than using it as energy or reducing intake. The original idea about why this happens was that obese people ate too much, and if they correct this behavioral problem they will lose their extra fat. Newer ideas focus on the physiology of obesity and point to distinct endocrinological or inflammatory processes that drive energy intake towards fat storage rather than metabolism upregulation. There are competing ideas of the distal cause of this state and many seemingly paradoxical observations in obesity research. These observations will be integrated into an attempt at a unified theory of obesity. Topics will include:
2) Gut flora
3) Fatty acids, saturated and unsaturated
4) Hypothalamic inflammation
The Leptin Story
In 1994 Friedman et al. cloned the protein product of the so-called obese gene, leptin, which the genetically obese ob/ob mouse was deficient in 1. Humans deficient in this gene, too, present with obesity that is effectively treated with leptin injections 2. Likewise, earlier research showing obesity from lesion of specific hypothalamic nuclei (dorsomedial, paraventricular, lateral and arcuate) 3, was tied in with leptin as immunocytochemistry showed that so called “leptin receptors” were plentiful in those tissues 4. Although secreted by the stomach, placenta, and fetal tissues, the majority of leptin is secreted by white adipose 5. This supports a negative feedback theory whereby fat stores communicate to the hypothalamic energy balance system a state of energy repleteness. The target neurons then secrete neuropeptides that suppress appetite and increase metabolic rate. A mouse or human without the ability to produce leptin, or with damaged neuronal tissue unable to respond to it, loses this negative feedback, continuing to take in energy and store it as fat.
Leptin was seen as a promising treatment for obesity, until it was discovered that obese humans have very high circulating levels of leptin and injections did little to reduce their weight 6. This same phenomenon is seen in animal models of diet-induced obesity. At a molecular level, the protein phosphorylation events normally seen in leptin receptor binding 7,8 are disrupted in these “leptin resistant” animals. The term “leptin resistance” is borrowed from the Diabetes literature’s “insulin resistance.” In fact both phenomena are similar in a number of substantive ways. The receptors for insulin and leptin are both single transmembrane and homodimeric, are found in the same hypothalamic neuronal populations 9, and share downstream signaling proteins 10. Their effects are both related to energy balance and glycemia. Obesity treatment research has moved into compounds that “resensitize” neurons to leptin 11, similar to the thiazolidinedione drugs for Type II Diabetes; nothing has really come of this yet.
Another Side of Leptin
There is another aspect of leptin action that receives much less attention. The leptin receptor is a cytokine receptor 12 of the Type I family. This receptor family is shared by most of the interleukin and several chemokine (G-CSF, GM-CSF) receptors, the growth hormone receptor and the prolactin receptor. The crystalline structure of leptin is much more like interleukin 6 than it is like insulin. Also, like the interleukins, it has inflammatory or immune modulating effects 13. Leptin deficiency decreases the dose of lipopolysaccharide (LPS) needed for lethality in mice 14, and its secretion is upregulated by LPS 15.
Leptin has a similar character to the prostaglandins, which are associated with inflammation, but also considered to have necessary homeostatic functions 16. The inflammatory nature of leptin was completely absent from my formal training, which focused solely on the energy balance effects. At first this seemed strange, but upon reflection it’s the only way to present leptin within the current physiology paradigm. The genetically obese mouse, deficient in leptin, has its obesity reversed with leptin treatment. An absolute absence of leptin is associated strongly with obesity, and it’s presence with leanness. Inflammation, on the other hand, is associated with obesity, not with obesity reversal, making leptin’s inflammatory actions a paradox. How can something be necessary for energy balance and glucose tolerance, yet behave like molecules that cause obesity and insulin resistance? Leptin’s absence is only associated with obesity in one type of genetic mutant, however. In common, diet-induced obesity, leptin is present at high levels, in tandem with inflammation and insulin resistance. Is it simply being produced by impotent adipocytes vainly trying to communicate positive energy balance? Is it being produced at higher levels, as it is in LPS treatment, in response to obesity related inflammation? If so, why, and does leptin resistance have the same physiological consequences as its absence in genetic obesity?
The topic for Part II will be gut flora and obesity. There will be areas of overlap with this discussion on leptin, and this overlapping and linking will serve as the foundation, along with overlapping links with the subsequent topics, for the theoretical unification.
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