The Metabolic Consequences of Sleep Deprivation

Molecular inflammation: underpinnings of aging and age-related diseases.

During the past few decades, sleep curtailment has become a very common in industrialized countries. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity and diabetes. Evidence is rapidly accumulating to indicate that chronic partial sleep loss may increase the risk of obesity and diabetes. Laboratory studies in healthy volunteers have shown that experimental sleep restriction is associated with an adverse impact on glucose homeostasis. Insulin sensitivity decreases rapidly and markedly without adequate compensation in beta cell function, resulting in an elevated risk of diabetes. Prospective epidemiologic studies in both children and adults are consistent with a causative role of short sleep in the increased risk of diabetes. Sleep curtailment is also associated with a dysregulation of the neuroendocrine control of appetite, with a reduction of the satiety factor, leptin, and an increase in the hunger-promoting hormone, ghrelin. Thus, sleep loss may alter the ability of leptin and ghrelin to accurately signal caloric need, acting in concert to produce an internal misperception of insufficient energy availability. The adverse impact of sleep deprivation on appetite regulation is likely to be driven by increased activity in neuronal populations expressing the excitatory peptides orexins that promote both waking and feeding. Consistent with the laboratory evidence, multiple epidemiologic studies have shown an association between short sleep and higher body mass index after controlling for a variety of possible confounders.

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Associations between sleep loss and increased risk of obesity and diabetes

Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. It has been demonstrated that IR is associated with a state of chronic low-grade inflammation, and several mediators released from various cell types, including immune cells and adipocytes, have been identified as being involved in the development of IR. Among those are several pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, and various adipocytokines. Furthermore, several transcription factors and kinases such as c-Jun N-terminal kinase (JNK) and inhibitor of kappa B kinase-β (IKKβ), a kinase located proximal of nuclear factor-κB (NF-κB), participate in this process. Hepatocyte-specific overexpression of NF-κB is associated with IR and can mimic all features of fatty liver disease. Whereas the evidence for an important role of many pro-inflammatory pathways in IR in in vitro and animal studies is overwhelming, data from interventional studies in humans to prove this concept are still minor. As a complex network of inflammatory cytokines, adipocytokines, transcription factors, receptor molecules, and acute-phase reactants are involved in the development of IR, new therapeutic approaches in IR-related diseases will be based on a better understanding of their complex interactions.

Inflammatory mechanisms in the regulation of insulin resistance.

Background: Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later. Methods: A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted. Results: A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33–3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58 –2.35). Those with high SAD (25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98 – 3.81) vs those with low SAD (25 cm) and normal BMI (18.5–24.9 kg/m 2 ), whereas those both obese (BMI 30 kg/m 2 ) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI,

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Central obesity and increased risk of dementia more than three decades later

The mechanisms underlying leptin resistance are still being defined. We report here the presence in human blood of several serum leptin-interacting proteins (SLIPs), isolated by leptin-affinity chromatography and identified by mass spectrometry and immunochemical analysis. We confirmed that one of the major SLIPs is C-reactive protein (CRP). In vitro, human CRP directly inhibits the binding of leptin to its receptors and blocks its ability to signal in cultured cells. In vivo, infusion of human CRP into ob/ob mice blocked the effects of leptin upon satiety and weight reduction. In mice that express a transgene encoding human CRP, the actions of human leptin were completely blunted. We also found that physiological concentrations of leptin can stimulate expression of CRP in human primary hepatocytes. Recently, human CRP has been correlated with increased adiposity and plasma leptin. Thus, our results suggest a potential mechanism contributing to leptin resistance, by which circulating CRP binds to leptin and attenuates its physiological functions.

Hongbo Cai

Papers

Induction of leptin resistance through direct interaction of C-reactive protein with leptin.