Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes

Abstract

The neurotransmitter serotonin is an important regulator of energy balance. In the brain, serotonergic fibres from midbrain raphe nuclei project to key feeding centres, where serotonin acts on specific receptors to modulate the activity of various downstream neuropeptide systems and autonomic pathways and thus affects ingestive behaviour and energy expenditure. Serotonin, released by intestinal enterochromaffin cells, also appears to regulate energy homeostasis through peripheral mechanisms. Serotonergic effects on energy balance lead to secondary effects on glucose homeostasis, based on a well-established link between obesity and insulin resistance. However, serotonergic pathways may also directly affect glucose homeostasis through regulation of autonomic efferents and/or action on peripheral tissues. Several serotonergic compounds have been evaluated for clinical use in the treatment of obesity and type 2 diabetes; results of these trials are discussed here. Finally, future directions in the elucidation of serotonergic metabolic regulation are discussed.

Palatability Can Drive Feeding Independent of AgRP Neurons

“…Conversely, energy deprivation triggers increased activity of the neighboring neurons that make neuropeptide Y (NPY), agouti-related peptide (AgRP) and γ-aminobutyric acid (GABA) (AgRP neurons) resulting in increased inhibitory tone onto POMC neurons and competitive inhibition of melanocortin signaling at post-synaptic neurons located in many brain regions (Morton et al, 2006). Serotonin (5-hydroxytryptamine, 5-HT) is known to have anorexic properties and serotonergic drugs have been widely used as anti-obesity treatments (Lam and Heisler, 2007). Serotonergic innervation of ARC neurons mediates the satiety action of serotonin through the concerted activation of POMC neurons and inhibition of AgRP neurons (Heisler et al, 2006).…”

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

“…The centrally expressed serotonin 2C (5-HT2C) receptor, in particular, has been shown to stimulate satiety via excitatory neurotransmission [29][30][31][32][33][34]43 . Indeed, a large amount of literature has validated the critical role played by the 5-HT2C receptor, which has substantiated this receptor as a viable target for the development of therapeutics in appetite control and weight…”

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

“…The SERT is highly abundant in the cell membranes of peripheral tissues and neuronal synapses, and 5-HT is mainly stored in enterochromaffin cells and platelets [41] . Paroxetine increased serum 5-HT levels through inhibiting the reuptake of 5-HT by these cells.…”