*2.3.3 LH*

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

#### **Figure 4.**

*Neurons downstream of NPY/AgRP neurons in the ARC. NPY/AgRP neurons in the ARC send axons to multiple brain areas. Optogenetic stimulation of NPY/AgRP neurons in the ARC that innervate the BNST, PVH, or LH induces a robust feeding response. Neurons that express melanocortin receptors in the VMH regulate metabolism in peripheral tissues. Tonic inhibition of PBN neurons by NPY/AgRP neurons is necessary for maintenance of a normal feeding level.*

regulate the activity of these neurons. Orexin neurons and MCH neurons have multiple functions including regulation of both the sleep-wake cycle and motivated behaviors [38].

In addition to orexin neurons and MCH neurons, some glutamatergic and GABAergic neurons in the LH were found to regulate feeding [38], with activation of GABAergic neurons increasing food intake and that of glutamatergic neurons inhibiting it.

The LH is a unique hypothalamic area in that it interacts with the reward system including dopaminergic neurons in the ventral tegmental area that connect to the nucleus accumbens and striatum [38]. Both glutamatergic and GABAergic neurons in the LH regulate the reward system.

We recently showed that glutamatergic neurons of the LH regulate sweet and bitter taste sensitivities in response to changes in whole-body energy levels [39]. We found that fasting-induced activation of NPY/AgRP neurons in the ARC of mice increases the sensitivity to sweet taste and inhibits that to bitter taste through inhibition of distinct glutamatergic neurons in the LH.

#### *2.3.4 PBN*

Feeding can be suppressed via two mechanisms. One is mediated by satiety signals to regulate the physiological feeding cycle, and the other is mediated by anorexic signals such as abdominal pain or cancer cachexia. The PBN contributes to both mechanisms [29, 40–42]. As mentioned above (Section 2.2.3), GDF15 induced anorexia is mediated by the PBN. Neural signals from the gut associated with suppression of food intake are mediated by afferent nerve fibers in the vagus

**9**

**Figure 5.**

*in the VMH.*

*Neural Control of Homeostatic Feeding and Food Selection*

nerve, the NTS, and then the PBN. Recent studies have revealed that anorexic signals are mediated by calcitonin gene-related peptide (CGRP) expressing neurons in the PBN, whereas satiety signals are mediated by non-CGRP neurons

NPY/AgRP neurons in the ARC constitutively inhibit CGRP neurons in the PBN through a GABAergic signal [29]. Ablation of these NPY/AgRP neurons in adult mice thus activates the CGRP neurons and halts feeding, thereby leading to starvation and death. Injection of GABA into the PBN, however, allows the mice to resume feeding and to survive. Furthermore, forced feeding of the mice with a liquid meal via a stomach tube for 1 week results in the recovery of food intake to normal levels, likely as a consequence of the rearrangement of neural circuits in the PBN. Neural circuits that converge on the PBN were recently found to encode competing danger

As described above (Section 2.1), the activity of NPY/AgRP neurons in the ARC is rapidly suppressed not only by actual feeding but also by food values, suggesting that these neurons are regulated by upstream neurons in the brain as well as by nutrient signals transmitted via the NTS and afferent nerves in the vagus nerve (**Figure 5**). Thyrotropin-releasing hormone (TRH)- or pituitary adenylate cyclaseactivating polypeptide (PACAP)-expressing glutamatergic neurons in the PVH have been shown to activate NPY/AgRP neurons in the ARC and to increase food intake [11]. In contrast, GABAergic neurons in the DMH inhibit NPY/AgRP neurons [11]. POMC neurons in the ARC are also activated by glutamatergic neurons in

*Neurons upstream of NPY/AgRP neurons in the ARC. TRH- or PACAP-expressing glutamatergic neurons in the PVH activate NPY/AgRP neurons in the ARC and increase food intake. In contrast, GABAergic neurons in the DMH inhibit NPY/AgRP neurons. POMC neurons in the ARC are also activated by glutamatergic neurons* 

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

signals such as fear and pain [40, 41].

**2.4 Upstream neurons that regulate NPY/AgRP neurons**

in the PBN [29, 40–42].

the VMH [43].

*Neural Control of Homeostatic Feeding and Food Selection DOI: http://dx.doi.org/10.5772/intechopen.93413*

*New Insights into Metabolic Syndrome*

regulate the activity of these neurons. Orexin neurons and MCH neurons have multiple functions including regulation of both the sleep-wake cycle and motivated

*Neurons downstream of NPY/AgRP neurons in the ARC. NPY/AgRP neurons in the ARC send axons to multiple brain areas. Optogenetic stimulation of NPY/AgRP neurons in the ARC that innervate the BNST, PVH, or LH induces a robust feeding response. Neurons that express melanocortin receptors in the VMH regulate metabolism in peripheral tissues. Tonic inhibition of PBN neurons by NPY/AgRP neurons is necessary* 

In addition to orexin neurons and MCH neurons, some glutamatergic and GABAergic neurons in the LH were found to regulate feeding [38], with activation of GABAergic neurons increasing food intake and that of glutamatergic neurons

The LH is a unique hypothalamic area in that it interacts with the reward system including dopaminergic neurons in the ventral tegmental area that connect to the nucleus accumbens and striatum [38]. Both glutamatergic and GABAergic neurons

We recently showed that glutamatergic neurons of the LH regulate sweet and bitter taste sensitivities in response to changes in whole-body energy levels [39]. We found that fasting-induced activation of NPY/AgRP neurons in the ARC of mice increases the sensitivity to sweet taste and inhibits that to bitter taste through

Feeding can be suppressed via two mechanisms. One is mediated by satiety signals to regulate the physiological feeding cycle, and the other is mediated by anorexic signals such as abdominal pain or cancer cachexia. The PBN contributes to both mechanisms [29, 40–42]. As mentioned above (Section 2.2.3), GDF15 induced anorexia is mediated by the PBN. Neural signals from the gut associated with suppression of food intake are mediated by afferent nerve fibers in the vagus

**8**

behaviors [38].

**Figure 4.**

inhibiting it.

*2.3.4 PBN*

in the LH regulate the reward system.

*for maintenance of a normal feeding level.*

inhibition of distinct glutamatergic neurons in the LH.

nerve, the NTS, and then the PBN. Recent studies have revealed that anorexic signals are mediated by calcitonin gene-related peptide (CGRP) expressing neurons in the PBN, whereas satiety signals are mediated by non-CGRP neurons in the PBN [29, 40–42].

NPY/AgRP neurons in the ARC constitutively inhibit CGRP neurons in the PBN through a GABAergic signal [29]. Ablation of these NPY/AgRP neurons in adult mice thus activates the CGRP neurons and halts feeding, thereby leading to starvation and death. Injection of GABA into the PBN, however, allows the mice to resume feeding and to survive. Furthermore, forced feeding of the mice with a liquid meal via a stomach tube for 1 week results in the recovery of food intake to normal levels, likely as a consequence of the rearrangement of neural circuits in the PBN. Neural circuits that converge on the PBN were recently found to encode competing danger signals such as fear and pain [40, 41].

## **2.4 Upstream neurons that regulate NPY/AgRP neurons**

As described above (Section 2.1), the activity of NPY/AgRP neurons in the ARC is rapidly suppressed not only by actual feeding but also by food values, suggesting that these neurons are regulated by upstream neurons in the brain as well as by nutrient signals transmitted via the NTS and afferent nerves in the vagus nerve (**Figure 5**). Thyrotropin-releasing hormone (TRH)- or pituitary adenylate cyclaseactivating polypeptide (PACAP)-expressing glutamatergic neurons in the PVH have been shown to activate NPY/AgRP neurons in the ARC and to increase food intake [11]. In contrast, GABAergic neurons in the DMH inhibit NPY/AgRP neurons [11]. POMC neurons in the ARC are also activated by glutamatergic neurons in the VMH [43].

#### **Figure 5.**

*Neurons upstream of NPY/AgRP neurons in the ARC. TRH- or PACAP-expressing glutamatergic neurons in the PVH activate NPY/AgRP neurons in the ARC and increase food intake. In contrast, GABAergic neurons in the DMH inhibit NPY/AgRP neurons. POMC neurons in the ARC are also activated by glutamatergic neurons in the VMH.*
