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CNS Targets of Adipokines

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Our understanding of adipose tissue as an endocrine organ has been transformed over the last 20 years. During this time, a number of adipocyte‐derived factors or adipokines have been identified. This article will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS‐mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted. © 2017 American Physiological Society. Compr Physiol 7:1359‐1406, 2017.

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Figure 1. Figure 1. Leptin‐signaling in leptin‐sensitive compared with leptin‐resistant conditions. Leptin‐sensitive: Upon leptin binding to the extracellular domain of the receptor dimer, Janus kinase (JAK) 2 is activated resulting in phosphorylation of the intracellular domain of receptor at three tyrosine residues: (i) phosphorylation of Tyr985 resulting in recruitment of Src‐homology 2 domain‐containing phosphatase 2 (SHP2/PTPN1) leading to activation of the extracellular signal‐regulated kinases (ERK) signaling cascade (30,89,357); (ii) phosphorylation of Tyr1077 resulting in recruitment of the transcription factor Signal transducer and activator of transcription (STAT) 5 (219); and (iii) phosphorylation of Tyr1138 resulting in recruitment of the transcription factor STAT3 (30,357,579). Activation of Ob‐Rb signaling also can result in activation of the phosphatidylinositol 3‐kinase (PI3K) pathway via insulin receptor substrate (IRS) proteins (160,480). Negative feedback inhibition of Ob‐Rb signaling is provided by suppressor of cytokine signaling (SOCS) 3 (53,55,164) binding at Try985 and PTP1B acting at Jak2 (106,628). Leptin‐resistant: Diet‐induced obesity causes inflammation and ER stress in the brain (143,438,561,635). Obesity‐associated inflammation and ER stress activate the nuclear factor‐kappa B (NFκB) signaling pathway and c‐Jun N‐terminal kinase (JNK) in the brain (635). JNK inhibits IRS signaling. In the course of normal homeostatic leptin signaling, negative feedback inhibition of Ob‐Rb signaling is provided by SOCS3 (53,55,164) and PTP1B binding (106,628). Obesity is associated with elevated hypothalamic expression of both SOCS3 (53) and PTP1B (629). Expression of PTP1B is increased by inflammation (629) and ER stress (443) via the activation of NFkB signaling providing a further potential mechanistic link between inflammatory signaling and ER stress and the development of CNS leptin resistance. Solid blue arrows indicate activation; dashed blue arrows indicate nuclear translocation; and red lines indicate an inhibitory action.
Figure 2. Figure 2. Simplified diagram of CNS neurocircuits regulating energy and glucose homeostasis. A number of hypothalamic and extrahypothalamic sites have been implicated in the action of leptin in the regulation energy and glucose homeostasis. Due to the extensive neuronal interconnectivity between the brain nuclei in the diagram, for clarity, the neural projections between each site have not been indicated. The hypothalamic ARC contains neuropeptide Y and agouti‐related peptide (NPY/AgRP) neurons that stimulate food intake and are inhibited by leptin, and proopiomelanocortin (POMC) neurons that reduce food intake and are stimulated by leptin. NPY/AgRP neurons also inhibit POMC neurons via synaptic release of the neurotransmitter GABA. POMC and AgRP neurons exert their effects on food intake via melanocortin 4 receptors (MC4R) expressed on downstream target neurons. ARC, arcuate nucleus; LepRb, leptin receptor; Mc3r/Mc4r, melanocortin‐3/4 receptor; VMH, ventromedial hypothalamus; LHA, lateral hypothalamic area; PVN, paraventricular nucleus; DMH, dorsomedial hypothalamus; VTA, ventral tegmental area; NTS, nucleus of the solitary tract. Reprinted with permission from (410).
Figure 3. Figure 3. Simplified schematic of adiponectin receptor signaling. AdipoR1/2 interacts with the adaptor protein APPL1 stimulating the insulin receptor substrate 1/2 (IRS1/2) pathway leading to increased Akt (serine 473), Foxo1 (serine 256), and ERK (threonine 202/tyrosine 204) phosphorylation. Activation of the receptor can also stimulate the JAK2‐STAT3 pathway, increasing STAT3 tyrosine 705 phosphorylation, translocation of dimerized STAT3 to the nucleus and activation of transcription. The adipokine can also activate the AMP‐activated protein kinase (AMPK) via increasing intracellular calcium levels, leading to activation of calmodulin‐dependent kinase kinase β (CamKKβ). Phosphorylation of AMPK (threonine 172) by CamKKβ, increases kinase activity and subsequent leads to phosphorylation of endothelial nitric oxide synthase (eNOS) at serine 1177 by AMPK. Adiponectin can also stimulate the stress activated MAP kinase pathway by stimulating phosphorylation of p38 MAPK.

Figure 1. Leptin‐signaling in leptin‐sensitive compared with leptin‐resistant conditions. Leptin‐sensitive: Upon leptin binding to the extracellular domain of the receptor dimer, Janus kinase (JAK) 2 is activated resulting in phosphorylation of the intracellular domain of receptor at three tyrosine residues: (i) phosphorylation of Tyr985 resulting in recruitment of Src‐homology 2 domain‐containing phosphatase 2 (SHP2/PTPN1) leading to activation of the extracellular signal‐regulated kinases (ERK) signaling cascade (30,89,357); (ii) phosphorylation of Tyr1077 resulting in recruitment of the transcription factor Signal transducer and activator of transcription (STAT) 5 (219); and (iii) phosphorylation of Tyr1138 resulting in recruitment of the transcription factor STAT3 (30,357,579). Activation of Ob‐Rb signaling also can result in activation of the phosphatidylinositol 3‐kinase (PI3K) pathway via insulin receptor substrate (IRS) proteins (160,480). Negative feedback inhibition of Ob‐Rb signaling is provided by suppressor of cytokine signaling (SOCS) 3 (53,55,164) binding at Try985 and PTP1B acting at Jak2 (106,628). Leptin‐resistant: Diet‐induced obesity causes inflammation and ER stress in the brain (143,438,561,635). Obesity‐associated inflammation and ER stress activate the nuclear factor‐kappa B (NFκB) signaling pathway and c‐Jun N‐terminal kinase (JNK) in the brain (635). JNK inhibits IRS signaling. In the course of normal homeostatic leptin signaling, negative feedback inhibition of Ob‐Rb signaling is provided by SOCS3 (53,55,164) and PTP1B binding (106,628). Obesity is associated with elevated hypothalamic expression of both SOCS3 (53) and PTP1B (629). Expression of PTP1B is increased by inflammation (629) and ER stress (443) via the activation of NFkB signaling providing a further potential mechanistic link between inflammatory signaling and ER stress and the development of CNS leptin resistance. Solid blue arrows indicate activation; dashed blue arrows indicate nuclear translocation; and red lines indicate an inhibitory action.

Figure 2. Simplified diagram of CNS neurocircuits regulating energy and glucose homeostasis. A number of hypothalamic and extrahypothalamic sites have been implicated in the action of leptin in the regulation energy and glucose homeostasis. Due to the extensive neuronal interconnectivity between the brain nuclei in the diagram, for clarity, the neural projections between each site have not been indicated. The hypothalamic ARC contains neuropeptide Y and agouti‐related peptide (NPY/AgRP) neurons that stimulate food intake and are inhibited by leptin, and proopiomelanocortin (POMC) neurons that reduce food intake and are stimulated by leptin. NPY/AgRP neurons also inhibit POMC neurons via synaptic release of the neurotransmitter GABA. POMC and AgRP neurons exert their effects on food intake via melanocortin 4 receptors (MC4R) expressed on downstream target neurons. ARC, arcuate nucleus; LepRb, leptin receptor; Mc3r/Mc4r, melanocortin‐3/4 receptor; VMH, ventromedial hypothalamus; LHA, lateral hypothalamic area; PVN, paraventricular nucleus; DMH, dorsomedial hypothalamus; VTA, ventral tegmental area; NTS, nucleus of the solitary tract. Reprinted with permission from (410).

Figure 3. Simplified schematic of adiponectin receptor signaling. AdipoR1/2 interacts with the adaptor protein APPL1 stimulating the insulin receptor substrate 1/2 (IRS1/2) pathway leading to increased Akt (serine 473), Foxo1 (serine 256), and ERK (threonine 202/tyrosine 204) phosphorylation. Activation of the receptor can also stimulate the JAK2‐STAT3 pathway, increasing STAT3 tyrosine 705 phosphorylation, translocation of dimerized STAT3 to the nucleus and activation of transcription. The adipokine can also activate the AMP‐activated protein kinase (AMPK) via increasing intracellular calcium levels, leading to activation of calmodulin‐dependent kinase kinase β (CamKKβ). Phosphorylation of AMPK (threonine 172) by CamKKβ, increases kinase activity and subsequent leads to phosphorylation of endothelial nitric oxide synthase (eNOS) at serine 1177 by AMPK. Adiponectin can also stimulate the stress activated MAP kinase pathway by stimulating phosphorylation of p38 MAPK.
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Teaching Material

C. Beall, L. Hanna, K. L. J. Ellacott. CNS Targets of Adipokines. Compr Physiol 7: 2017, 1359-1406. doi:10.1002/cphy.c160045

Didactic Synopsis

Major Teaching Points:

  1. In addition to storing excess energy as triglyceride, adipose tissue is an important endocrine organ secreting factors called adipokines into the circulation that act on their receptor targets in distant tissues, including the CNS.
  2. Leptin is a key adipokine, which acts on target receptors throughout the brain to signal how much energy the body has stored.
    1. Obesity (excess adipose tissue) is associated with high levels of circulating leptin.
    2. Reduced circulating leptin is a key signal for the activation of CNS pathways, which promote weight gain, including increased food intake and reduced energy expenditure.
    3. Leptin acting in the brain also regulates the activity of other neuroendocrine axes including the reproductive axis and the thyroid hormone axis, and can also regulate cardiovascular function.
  3. Other adipokines that act in the CNS to modulate physiological processes include adiponectin, resistin, apelin, visfatin, and adipocyte-derived cytokines.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Leptin signals through a tyrosine kinase linked receptor. The signaling mechanism is described in the formal figure legend. Phosphorylation of different tyrosine residues on the intracellular domain of the leptin receptor results in the activation of different downstream signaling pathways including kinases and transcription factors. These subsequently mediate a number of different downstream physiological events including modulation of neuroendocrine and autonomic pathways. Feedback inhibition of leptin receptor signaling is mediated via SOCS 3 and PTP1B. When leptin levels are chronically elevated during obesity leptin signaling becomes less effective: a state known as leptin resistance. On a molecular level inflammation and ER stress associated with obesity lead to an enhancement of the inherent mechanisms inhibiting leptin signaling (SOCS3 and PTP1B) and also stimulation of JNK which inhibits leptin signaling via the IRS/PI3K pathway.

Figure 2. Teaching points: Leptin receptors are found in many different areas of the brain and important in regulating the regulation of food intake and body weight (energy homeostasis), and the control of blood glucose levels. This includes a number of areas within the hypothalamus but also non-hypothalamic areas of the brain including sites in the midbrain (VTA) and brainstem (NTS). The most well characterized and understood effects of leptin on glucose and energy homeostasis occur via its receptors expressed in the hypothalamus. In an area of the hypothalamus called the arcuate nucleus (ARC) neurons containing neuropeptide Y and agouti-related peptide [(NPY/AgRP) that stimulate food intake], and neurons containing proopiomelanocortin [(POMC) that reduce food intake]; both express leptin receptors. Leptin acts to decrease food intake by inhibiting the activity of NPY/AgRP neurons and increasing the activity of POMC neurons. Melanocortin 4 receptors (MC4R) are important for mediating the downstream effects of POMC and NPY/AgRP neurons on food intake. In humans and animals, mutations in the POMC or MC4R gene cause profound obesity.

Figure 3. Teaching points: Adiponectin receptors (AdipoR1/2) are seven transmembrane receptors but are not G-protein coupled. Activation of adiponectin receptors by adiponectin can lead to the activation of a number downstream signaling pathways, as described in the main figure legend. This includes kinases and transcription factors. AMPK, which is activated downstream of adiponectin receptors is a critical enzyme in the modulation of cellular energy levels regulating fatty acid uptake and β-oxidation.

Related Articles:

Autonomic nervous system and adipose tissue
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How to Cite

Craig Beall, Lydia Hanna, Kate L. J. Ellacott. CNS Targets of Adipokines. Compr Physiol 2017, 7: 1359-1406. doi: 10.1002/cphy.c160045