Serotonin Improves High Fat Diet Induced Obesity in Mice

Animal studies are not the usual coverage topic of brainscienceblogs.com. However, in this instance, we could not resist.

Serotonin (5-HT) is a monoaminergic neurotransmitter with activities that modulate central and peripheral functions. The first step in the synthesis of 5-HT from tryptophan depends on the enzyme tryptophan hydroxylase (TPH), which is also the rate-limiting enzyme in its biosynthesis. TPH is known to possess two isoforms, TPH1 and TPH2 [1]. TPH1 is mostly present in the pineal gland, spleen, thymus and intestinal enterochromaffin cells. TPH2 is expressed entirely in neuronal cells, such as in the raphe nuclei of the brain stem. Peripheral 5-HT in TPH1 knockout mice is not able to be replaced with 5-HT synthesized by TPH2 in the central nervous system [2]. Further, it is thought that 5-HT in the periphery cannot pass the blood-brain barrier [3, 4]. Thus, there are two independent systems of organization for 5HT: one in the central nervous system and the other in the periphery. 5-HT affects feeding behavior and obesity in the central nervous system, and close to 2% of the body’s 5-HT is stored there [5–10]. On the other hand, peripheral 5-HT has not been the subject of such intense study, particularly with respect to body fat and lipid metabolism, even though approximately 98% of the body’s 5-HT exists in the periphery.

Accumulating evidence indicates that peripheral 5-HT plays an important role in glucose and lipid metabolism. Recent studies have shown that the level of blood 5-HT and the number of intestine enterochromaffin cells in obese mice was found to be much higher than that in lean mice [11, 12]. Intraperitoneal (i.p.) injection of 5-HT to mice accelerates the metabolism of lipid by increasing the concentration of circulating bile acids [13], and further, that 5-HT regulates fat metabolism and feeding behavior through independent molecular mechanisms inCaenorhabditis elegans [14]. Additionally, TPH1 deficient mice have an impaired insulin secretion and significantly higher blood glucose concentrations than wild type animals in glucose tolerance tests [15]. On the other hand, gut-derived serotonin enhances lipolysis in adipocytes through 5-HT receptor (5HTR) 2B and gluconeogenesis in hepatocytes through 5HTR2B [16]. TPH1 deficient mice are protected from obesity and insulin resistance by elevation of brown adipose tissue activity [17]. These studies suggest that 5-HT may be a key factor with regard to glucose and lipid metabolism, fat accumulation and obesity in not only the central nervous system but also the periphery, as demonstrated through the various phenotypes of available knock out mice.

Skeletal muscle has important roles in energy metabolism and glucose utilization, especially during excise. The existence of slow and fast type myosin heavy chain isoforms is observed in normal mature muscle fibers. Slow type muscle fibers have a high concentration of mitochondria and produce energy by oxidative metabolism. In contrast, fast type muscle fibers use glycolysis as the chief ATP source [18, 19]. Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1 a (PGC-1a), is identified as a nuclear receptor coactivator of PPARγ, and it is a principal physiological regulator for slow type muscle fiber specification [19–21]. Skeletal muscle–specific PGC-1α knockout mice have significantly impaired glucose tolerance [22], while obese humans have a significantly lower percentage of slow type muscle fibers than humans with lower adiposities [23].

It is strongly suggested that 5-HT may be a key factor with regard to energy metabolism in skeletal muscle, as recent study shows that a 5HTR2 agonist induces the elevation of PGC-1α promoter activity [24]. To verify these hypotheses, we investigated the effect of long-term treatment of mice with peripheral 5-HT on obesity and energy metabolism in skeletal muscle in mice on the high fat diet.