Figure 2. The interactions between the neuropeptides in the hypothalamus regulating energy homeostasis and its alteration in tubby mice.

Signals related to diet and circulating nutrients (shown at the bottom), which stimulate (+) or inhibit (−) the production of peptides, are received by the various hormonal receptors in the ARC nuclei, which contain NPY/AGRP- and POMC/CART-producing groups of cells. The activation of NPY/AGRP neurons promotes food intake, whereas POMC/CART neurons have the opposite effect. Both signals project onto LHA neurons that express MCH and orexin (important stimulators of food intake), which are also mediated by dopamine, serotonin and endocannabinoids. The loss of the TUB function in tubby mice causes alteration in the expression of different neuropeptides, such as AGRP, NPY and POMC in ARC, as well as upregulation of NPY by ∼30-fold in DMH/VMH and orexin by ∼60-fold in LHA (highlighted in red). The image of tubby mice was provided by J.Naggert and P. Nishina (Nat. Genet. 39,149; 2007). Abbreviations: AGRP, agouti-related protein; ARC, arcuate nucleus; CART, cocaine–amphetamine-regulated transcript; DMH and VMH, dorsomedial and ventromedial hypothalamus; LHA, lateral hypothalamus; MCH, melanin-concentrating hormone; NPY neuropeptide Y; POMC, pro-opiomelanocortin.