*2.3.1 PVH*

*New Insights into Metabolic Syndrome*

*2.2.2 Asprosin*

*2.2.3 GDF15*

amino acids, with a molecular mass of ~30 kDa.

of cancer or under conditions of severe stress.

mice, however, they are both reduced in asprosin knockout mice.

not able to reliably detect changes in neuronal activity in the hypothalamus. Indeed, NPY/AgRP neurons and POMC neurons are reciprocally regulated in the ARC, which itself constitutes only a small proportion of the hypothalamus, making it difficult to study such changes in neuronal activity. However, given that individuals with a mutation of the POMC gene manifest hyperphagia and obesity similar to those of mutant mice, NPY/AgRP neurons and POMC neurons play an important role in feeding behavior and metabolic control in humans as well as rodents.

Ghrelin is a peptide released from the stomach and has a unique structure in that it is octanoylated at its third amino acid residue (serine) [22], with this acylation being essential for the orexigenic and metabolic effects of ghrelin. Ghrelin induces feeding by actions in the brain, including the activation of NPY/AgRP neurons and suppression of POMC neurons in the ARC. Until the discovery of asprosin, ghrelin was the only orexigenic peripheral hormone known. In humans, the plasma level of ghrelin increases immediately before breakfast, lunch, and dinner and declines after feeding. Fasting and anorexia nervosa are associated with an increased circulating concentration of ghrelin. Although ghrelin markedly stimulates feeding, its physiological function remains unknown because feeding and energy metabolism are largely unaffected in ghrelin knockout mice. It may contribute to the alert system for promotion of feeding at scheduled times such as breakfast, lunch, and dinner.

Asprosin was recently identified as an orexigenic hormone that is released from adipose tissue and which activates NPY/AgRP neurons in the ARC [2]. The name asprosin is derived from the Greek word for white (aspros) because the hormone is produced by white adipose tissue. Asprosin is a protein hormone composed of 140

Asprosin was discovered as a result of the study of Marfan lipodystrophy syndrome, which is caused by mutation of the profibrillin 1 gene (*FBN1*) and is characterized by congenital lipodystrophy and a neonatal progeroid appearance as well as by severe anorexia and leanness. It differs from the lipodystrophy associated with severe insulin resistance, type 2 diabetes, and hyperphagia, suggesting that leptin is not involved. Asprosin was found to be encoded by the 3′-terminal region of *FBN1*, and the protease furin produces asprosin and fibrillin by cleaving profibrillin 1. Asprosin stimulates gluconeogenesis in the liver [27]. Similar to that of ghrelin, the plasma level of asprosin increases during fasting and decreases after refeeding. Whereas food intake and body weight remain largely unaltered in ghrelin knockout

GDF15 is a member of the transforming growth factor-β family of proteins and exists in blood [3]. The amount of GDF15 mRNA is highest in adipose tissue, followed by skeletal muscle and bone marrow, and the GDF15 receptor, glial cell-derived neurotrophic factor receptor like (GFRAL), is expressed in the area postrema (AP), another brain area with a minimally effective blood-brain barrier. GDF15 activates GFRAL in the AP and thereby reduces food intake via the nucleus tractus solitarius (NTS)-parabrachial nucleus (PBN) pathway. GDF15 is likely a physiological regulator of feeding, given that both GDF15 and GFRAL knockout mice have an increased body weight. Furthermore, GDF15 may play a role in cancer or in stress-induced anorexia because its plasma level is increased in animal models

**6**

The PVH is an important area in the control of feeding. It contains many secondary neurons that are regulated by NPY/AgRP neurons and POMC neurons in the ARC [1, 11, 21]. Given that NPY, AgRP, and GABA—neurotransmitters or neuromodulators released from NPY/AgRP neurons—all act at inhibitory receptors, activation of NPY/AgRP neurons stimulates feeding via suppression of these secondary neurons. NPY/AgRP neurons were found to increase food intake via MC4R-expressing neurons in the PVH [30], and more recent studies showed that oxytocin- or GLP-1 receptor-expressing neurons in the PVH induce feeding through PBN neurons [31, 32].
