*2.2.2 Asprosin*

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

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

## *2.2.3 GDF15*

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 of cancer or under conditions of severe stress.

**7**

energy metabolism.

*2.3.3 LH*

*Neural Control of Homeostatic Feeding and Food Selection*

**2.3 Downstream neurons regulated by NPY/AgRP neurons**

NPY/AgRP neurons and POMC neurons in the ARC are connected to many brain areas. In particular, connections between these neurons and the PVH, lateral nucleus of the hypothalamus (LH), dorsomedial nucleus of the hypothalamus (DMH), VMH, BNST, and PBN are important neural pathways for regulation of food intake and metabolism (**Figure 4**). Optogenetic activation of projections of NPY/AgRP neurons to the PVH, LH, and BNST has been shown to increase food intake [28]. In addition, the PBN has been found to be necessary for maintenance of a normal level of food intake [29]. I will address the role of the PVH, VMH, LH, and

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

The VMH is known as the satiety center. Indeed, activation of VMH neurons expressing the transcription factor SF1 (steroidogenic factor 1) reduces food intake and increases energy expenditure in mice [33]. VMH neurons including some SF1 neurons express MC4R or MC3R, suggesting that NPY/AgRP neurons and POMC neurons in the ARC regulate VMH neurons. We recently showed that activation of SF1-expressing neurons in the VMH by DREADD (designer receptors exclusively activated by designer drugs) technology not only reduces food intake and increases energy expenditure but also increases glucose uptake in certain peripheral tissues including interscapular brown adipose tissue, skeletal muscle, and the heart [33]. We have also shown that leptin increases insulin sensitivity in peripheral tissues as well as glucose utilization by the whole body through the VMH [34, 35]. Furthermore, we revealed that the hypothalamic neuropeptide orexin activates VMH neurons and thereby increases both insulin sensitivity and glucose utilization in skeletal muscle, with the orexin-VMH system being activated by taste stimulation and feeding [36]. These observations suggest that the orexin-VMH system preferentially increases glucose uptake in skeletal muscle during feeding. However, the physiological role of VMH neurons remains elusive, with further investigation being necessary to explore their contribution to the regulation of whole-body

The LH is known as the feeding center given that some neurons of this area contribute to the control of feeding. Activation of orexin neurons and melaninconcentrating hormone (MCH) neurons of the LH and perifornical area thus increases food intake [37], and NPY/AgRP neurons and POMC neurons in the ARC

*DOI: http://dx.doi.org/10.5772/intechopen.93413*

PBN in the regulation of food intake.

through PBN neurons [31, 32].

*2.3.1 PVH*

*2.3.2 VMH*
