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Home , Adiponectin, Neuropeptide Y, Obestatin, Pancreatic polypeptide, Peptide YY

1 Neuroendocrine factors

2 In Figure 1 and Table 1, information about the function and site of action of variable neuroendocrine

3 factors is summarized. For this review, neuroendocrine factors are grouped according to their main

4 action: stimulation of food intake and/or increase in body weight or inhibition of food intake and/or

5 decrease in body weight. The order of presentation is based on the number of studies about the

6 respective neuroendocrine factor.

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8 Neuroendocrine factors that stimulate food intake and/or increase body weight

9 Several neuroendocrine factors are involved in the stimulation of food intake and increase of body

10 weight.

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12

13 Ghrelin, also known as the “ ” is a polypeptide hormone mainly produced by

14 ghrelinergic cells in the gastric fundus and other parts of the when in fasting

15 state. Ghrelin stimulates food intake and gastric emptying. It regulates ,

16 stimulates lipogenesis and inhibits lipid oxidation. In addition, it stimulates growth

17 hormone release. In the , ghrelin stimulates agouti-related in the

18 of the hypothalamus, thereby inhibiting the 4 in the

19 paraventricular nucleus of the hypothalamus. The inhibition of the 4 results in

20 decreased satiety and increased . In the circulation, ghrelin consists of an acylated and an

21 unacylated form. Serum acylated ghrelin is unstable outside the body and at venipuncture, it rapidly

22 deacylates to unacylated ghrelin without addition of an esterase inhibitor. A pitfall in most studies is

23 that only total ghrelin is measured and not the more specific forms. With regard to the metabolic and

24 appetite regulating effect, acylated and unacylated ghrelin concentrations are more relevant than

25 total ghrelin. Acylated ghrelin binds to the secretagogue receptor in the and

26 and is considered a diabeteogenic peptide. It increases growth hormone ,

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27 appetite, food seeking behavior and accumulation. The role of unacylated ghrelin is still unknown,

28 but it might have anti-diabetogenic actions and acts as a functional inhibitor of acylated ghrelin,

29 suggesting that the ratio acylated/unacylated ghrelin might be more important than the individual

30 metabolites itself(1). In this review we use the term ghrelin for total ghrelin and AG and UAG for the

31 acylated and unacylated form of ghrelin, respectively.

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34 Adiponectin, an adipocytokine, is the most abundant peptide secreted by and regulates

35 glucose and lipid metabolism and . It has direct effect on the β-cells in the

36 pancreas, and has direct action in the , , and the vasculature. It also increases

37 sensitivity and has anti-inflammatory and anti-atherogenic characteristics. Serum

38 concentrations of adiponectin decrease with increasing body weight and are positively associated

39 with insulin sensitivity(2).

40 Studies in transgene-mediated overexpression of adiponectin in mouse models of deficiency

41 (ob/ob mice) show that chronic overexpression of adiponectin leads to a massive increase in

42 subcutaneous but not in visceral fat, and that it protects against diet induced (2).

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44 Brain derived neuroendocrine factors

45 Several regions in the brain are important in processing information about food and body weight, see

46 Figure 1. The nucleus of the tractus solitaries is the hindbrain area in which vagal and other neural

47 inputs are integrated. The arcuate nucleus at the base of the hypothalamus integrates leptin signals

48 by mutually changing the production and release of that increase food intake

49 ( Y and agouti-related peptide (AgRP)), and other peptides that decrease food intake

50 (-amphetamine-related transcript (CART) and (POMC)). The

51 paraventricular nucleus (PVN) has a central role in the regulation of food intake. It receives signals

52 from the peptides in the arcuate nucleus. The ventromedial and lateral hypothalamus are also part of

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53 the appetite regulating center. When the ventromedial hypothalamus is destructed, the activity of

54 the sympathetic nervous system will decline, leading to increased food intake and severe .

55 When the lateral hypothalamus is damaged, food intake and body weight may decrease. Also regions

56 of the may modulate food intake, either through connections to the ventromedial

57 hypothalamus or other connections.

58 Various are involved in these control centers in the brain, especially ,

59 agouti-related peptide, proopiomelanocortin, and cocaine-amphetamine-related transcript.

60

61 Neuropeptide Y

62 Neuropeptide Y is part of the peptide family. In the hypothalamus,

63 neuropeptide Y is one of the most abundant peptides and one of the most potent orexigenic factors.

64 The neuropeptide Y neurons in the arcuate nucleus in the hypothalamus project into the

65 paraventricular nucleus, hypothalamic nucleus, lateral hypothalamic area, and other hypothalamic

66 sites. The synthesis and secretion of neuropeptide Y are, among others, inhibited by leptin and

67 insulin, and stimulated by glucocorticoids and ghrelin. Neuropeptide Y suppresses the anorexigenic

68 effect of melanocortin signaling in the arcuate nucleus(3).

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70 Endocannabidoid system

71 The endocannabidoid system plays a critical role in energy homeostasis and is expressed in brain

72 areas such as the hypothalamus, the cortico-limbic system, the , and also in metabolically

73 active peripheral tissues. The most studied lipid ligands of the endocannabidoid system are the

74 endocannabinoids (N‐arachidonoyl‐ethanolamine, AEA) and 2‐arachidonoylglycerol (2‐

75 AG) which mainly act at the cannabinoid type 1 (CB1) receptors and in a lesser extent the

76 cannabinoid type2 (CB2) receptors(4). Activation of this system has mainly an anabolic effect by

77 stimulating food intake via the hedonic system and stimulating energy storage in liver and adipose

78 tissue and reducing lipolysis(4). The hedonic system refers to obtained pleasures of a certain

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79 behavior or sensation, e.g. hedonic hyperphagia is the drive to eat to obtain pleasure despite a lack

80 of hunger or an energy deficit.

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82 Beta-endorphin

83 Beta-endorphin is primarily synthesized and stored in the gland and is released in

84 response to -related secretion of corticotropin releasing hormone, and in response of pain and

85 exercise. Beta-endorphin has strong analgesic effects as an . Central

86 administration produces overeating in via the central nervous system(5). It has been shown that

87 the central effects of beta-endorphin on food intake are modulatory and play a main role in the

88 appetite initiating, goal-directed phase of feeding behavior. In this phase behavior can be most easily

89 adapted; i.e. indulge or resist the urge of food intake(6).

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91 Brain-derived neurotrophic factor

92 Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in the development and

93 plasticity of the central nervous system, in inflammation, metabolism, and cardiovascular disease(7).

94 In animal models with BDNF haploinsufficiency, hypothalamic expression of BDNF mRNA was

95 reduced, which caused hyperphagia and obesity and could be reversed by intracerebroventricular

96 infusions of BDNF(8). The loss of one copy of the BDNF , due to a deletion (e.g. 11p deletion or

97 as part of the Wilms tumor-aniridia syndrome) or by a chromosomal 11p inversion, is associated with

98 syndromic phenotypes linked to hyperphagia, childhood-onset obesity, intellectual disability and

99 impaired pain sensing (nociception)(9-11). In addition, the BDNFp.Val66Met single nucleotide

100 polymorphism has been associated with disorders such as nervosa or bulimia

101 nervosa(12).

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103 Agouti-related peptide

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104 Agouti-related peptide (AgRP) is an endogenous antagonist of melanocortin-3 and melanocortin-4

105 (MC4) receptors. In the hypothalamus, AgRP-expressing neurons co-express neuropeptide Y.

106 Centrally administered AgRP results in increased feeding in animal models. In humans, body mass

107 index correlates with the amount of AgRP and neuropeptide Y. The role of AgRP in appetite and body

108 weight homeostasis was recently reviewed by Baldini and Phelan(3).

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110 Neuroendocrine factors that inhibit food intake and/or decrease body weight

111 Several neuroendocrine factors are involved in the inhibition of food intake and decrease of body

112 weight.

113

114 Leptin

115 Leptin, an adipocytokine, is mainly secreted by white adipose tissue, and its concentrations are

116 positively correlated with the amount of body fat. Circulating plasma leptin concentrations reflect

117 primarily the amount of energy stored in fat and secondary the acute changes in caloric intake(13).

118 Leptin reduces food intake and energy metabolism by inhibition of the (LepR) in the

119 NPY neurons and stimulation of LepR in the POMC neurons in the arcuate nucleus.

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121 Pancreatic polypeptide family

122 The pancreatic polypeptide family includes the peptide YY (PYY), pancreatic polypeptide

123 (PP), and the neuropeptide Y (NPY). Peptide YY is produced in the ilial and colonic

124 cells and concentrations increase in response to a meal. Meal-stimulated peptide YY release occurs

125 mainly in response to ingested fat, predominantly short-chain and polyunsaturated fatty acids.

126 Peptide YY induces satiety by stimulating pro-opiomelanocortin neurons, inhibiting neuropeptide Y

127 and reducing gastric emptying. Two isoforms of peptide YY exist: peptide YY (1-36) and peptide YY (3-

128 36), the latter is highly specific for the neuropeptide Y 2 receptor in the arcuate nucleus where it

129 inhibits neuropeptide Y release, and thereby decreasing food intake. The pancreatic polypeptide (PP)

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130 is secreted by specific pancreatic islet cells. Pancreatic polypeptide concentrations increase

131 postprandially and also fluctuate with the myoelectric activity of the gastrointestinal tract.

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133

134 Cholecystokinin is produced in distinct endocrine cells that line the mucosa of the small intestine,

135 mainly in the and . Cholecystokinin stimulates gallbladder contraction, increases

136 pancreatic enzyme secretion, delays gastric emptying, potentiates insulin secretion, and regulates

137 food intake by inducing satiety. Cholecystokinin is rapidly released locally and into the in

138 response to nutrients in the gut, especially fat and protein(14). In a population based study, obese

139 carriers of variants in the cholecystokinin gene have an increased risk of eating large portion sizes(15).

140 Brain receptors for cholecystokinin (CCK1 and CCK2 receptors) are located in the lateral

141 hypothalamus, medial pons, and lateral medulla.

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143

144 Obestatin is formed by post‐translation modification of preproghrelin in the . In contrast to

145 ghrelin, it suppresses food intake. Obestatin administration to rats resulted in suppressed gastric

146 emptying and decreases body weight gain(16). Recent evidence suggests that obestatin also

147 augments insulin secretion, promotes pancreatic β‐cell survival and inhibits water intake in animal

148 models(17). However, there is still controversy whether obestatin plays an important role in the

149 brain-gut network in humans(18, 19).

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151

152 Neurotensin is a neuropeptide involved in the regulation of and prolactine

153 release and has significant interaction with the system. It is present throughout the

154 central nervous system, with highest concentrations in the hypothalamus, amygdala and nucleus

155 accumbens. It induces various effects, including analgesia, hypothermia and increased locomotor

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156 activity. In the periphery, neurotensin is dispersed in enteroendocrine cells of the small intestine,

157 where it inhibits gastric motility. The secretion of neurotensin is stimulated by food intake.

158

159 Proopiomelanocortin and its products

160 The proopiomelanocortin gene is expressed in many tissues, including the arcuate nucleus of the

161 hypothalamus, the pituitary gland, skin, and the immune system. Depending on the specific tissue,

162 proopiomelanocortin undergoes posttranslational cleavage, with the endproduct depending on the

163 endoproteases expressed in that tissue. The following peptides can be produced: adrenocorticotropic

164 hormone (ACTH), N-terminal peptide of proopiomelanocortin (pro-γ-MSH); α-, β-, and γ-

165 melanotropin (α-MSH, β-MSH, γ-MSH); corticotropin-like intermediate peptide; β- and γ-;

166 beta-endorphin; and [Met]-.

167 In human hypothalamus, leptin stimulates proopiomelanocortin conversion into α-melanotropin in

168 the arcuate nucleus. α-Melanotropin then binds to the Melanocortin 4 receptor (MC4R), a crucial

169 receptor involved in appetite control and energy homeostasis in the paraventricular nucleus and in

170 many other sites in the brain. Body weight changes are reported to be negatively associated with α-

171 melanotropin concentration in blood(20).

172

173 Cocaine-amphetamine-related transcript

174 Cocaine-amphetamine-related transcript is also an important hypothalamic regulator of satiety and it

175 inhibits food intake. It is coexpressed with proopiomelanocortin in the arcuate nucleus in animal

176 models, while in humans it is coexpressed with agouti-related peptide and neuropeptide Y(21).

177 Cocaine-amphetamine-related transcript expression is regulated by several other neuroendocrine

178 factors involved in appetite regulation, such as leptin, cholecystokinin and ghrelin. In rats, an

179 antiserum of cocaine-amphetamine-related transcript increases feeding, while intracerebro-

180 ventricular administration inhibits normal and starvation-related feeding and blocks the

181 neuropeptide Y feeding response(22).

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182

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