Obesity and dementia: adipokines interact with the brain

Abstract

Obesity is a pandemic and a serious global health concern. Obesity is a risk factor for multiple conditions and contributes to multi-morbidities, resulting in increased health costs and millions of deaths each year. Obesity has been associated with changes in brain structure, cognitive deficits, dementia and Alzheimer׳s disease. Adipokines, defined as hormones, cytokines and peptides secreted by adipose tissue, may have more widespread influence and functionality in the brain than previously thought. In this review, six adipokines, and their actions in the obese and non-obese conditions will be discussed. Included are: plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factors alpha (TNF-α), angiotensinogen (AGT), adiponectin and leptin. Their functionality in the periphery, their ability to cross the blood brain barrier (BBB) and their influence on dementia processes within the brain will be discussed.

Keywords: Adipokines; Alzheimer; Brain; Dementia; Leptin; Obesity.

Figure 1. Leptin resistance in obesity via SOCS-3 and JAK-2/STAT-3 pathway acurate nucleus of the hypothalamus

Leptin binding to LepRb activates the LepRb-associated JAK-2 tyrosine kinase (green arrows), leading to the autophosphorylation of tyrosine residues on JAK-2 and the phosphorylation of Tyr985 and Tyr1138 on the intracellular tail of LepRb (green arrows). Tyr985 and Tyr1138 are directly autophosphorylated after activation of LepRb, and phosphorylated Tyr1138 mediates the activation of the transcription factor STAT-3, and phosphorylated Tyr985 binds to SHP-2. Among other targets, STAT-3 induces the transcription of SOCS-3 during LepRb signalling in the nucleus (blue arrow). SOCS-3 is produced and released from the nucleus (grey arrow). The binding of phosphorylated Tyr985 to SHP-2 provides an important site of inhibition for SOCS-3 (red arrow). Furthermore, SOCS-3 inhibits STAT-3 and via binding to the LepRb-JAK-2 complex it attenuates LepRb-mediated signalling, and thereby LepRb-mediated signalling via the JAK-2/STAT-3 pathway. At high levels of circulating leptin as observed in obesity, LepRbs are highly activated and subsequently tyrosine residues are intensely phosphorylated. In case of LepRb this will lead to increased ‘leptin signalling’ via the JAK-2/STAT-3 pathway, while phosphorylation of the tyrosine residues will lead to increased expression of SOCS-3 which inhibits LepRb-mediated signalling. This inhibition could attenuate most of the expected increase in LepRb signalling, and explain leptin resistance in obesity. (Munzberg and Myers, 2005) Abbreviations: LepRb: Leptin receptor Rb; JAK-2: janus kinase 2; Tyr985/Tyr1138: tyrosine residues 985 and 1138; STAT-3: signal transducer and activator of transcription 3; P: phosphorylation; SHP-2: tyrosine-protein phosphatase non-receptor type 11; SOCS-3: suppressor of cytokine signaling 3; +: stimulation; -: inhibition

Figure 2. Effects of reviewed adipokines in the periphery and brain in obesity

Fat cells produce and secrete adipokines like, leptin (red), PAI-1 (blue), angiotensinogen (green), adiponectin (pink), TNF-α (turquoise) and IL-6 (purple). In the periphery, TNF-α and IL-6 stimulate inflammation; these adipokines trigger the liver to produce acute phase proteins. Adiponectin attenuates the inflammatory response by inhibiting the production of TNF-α and IL-6. Furthermore, adiponectin modulating inflammatory responses, energy expenditure (CNS and periphery), food intake (CNS) and a number of metabolic processes, including glucose regulation and fatty acid catabolism. Angiotensinogen increases blood pressure. PAI-1 inhibits fibrinolysis and also stimulates the inflammatory response. Leptin increases energy expenditure and decreases food intake. Only three adipokines discussed in this review are able to cross the BBB and affect, positively or negatively depending on concentration and environment, brain processes such as food intake, synaptic plasticity, learning and memory, and development of dementia. Furthermore, angiotensinogen, PAI-1, IL-6, TNF-α are also produced within the brain by neurons, astrocytes and microglia, and several theories exist that leptin and adiponectin might also be produced in the brain. Several studies reported that, within the brain, adiponectin can be involved in regulating food intake and neuroprotection, while angiotensinogen is involved in learning and memory processes and PAI-1 regulates among other neuroinflammation. Il-6 and TNF-α produced by astrocytes and microglia are involved in neurogenesis, neuroinflammation, synaptic plasticity and learning and memory processes. In obesity, the amount and function of adipokines are excessive, except for adiponectin and leptin. Adiponectin levels are decreased and it is hypothesized that leptin functionality could be decreased via leptin resistance. Therefore, obesity increases inflammation, increases blood pressure, and decreases fibrinolysis, energy expenditure and food intake in the periphery. In the brain, obesity results in impaired food intake, neurogenesis, synaptic plasticity and memory and learning processes possibly mediated through leptin, TNF-α and IL-6. Abbreviations: PAI-1: plasminogen activator inhibitor-1; IL-6: interleukin-6; TNF-α: tumor necrosis factor-alpha; CNS: central nervous system; BBB: blood brain barrier; +: increases/stimulates; -: decreases/inhibits