Trends in Endocrinology & Metabolism
ReviewNeuroinflammation and neurodegeneration in overnutrition-induced diseases
Section snippets
Overnutrition-induced diseases and neuroinflammation
Metabolic syndrome refers to a collection of interconnected disorders such as obesity, insulin resistance, glucose intolerance, hyperlipidemia, and hypertension, and the explosion of these problems has become a global health concern. Obesity is a driver of metabolic syndrome and a well-recognized risk factor for the development of T2D and related cardiovascular diseases (CVDs). Known as a chronic and pathologic outcome of excessive caloric intake and storage, obesity development is
Neuroinflammation in the hypothalamus
Research during the past decades has focused on examining peripheral tissues relevant to the pathogenesis of obesity and related diseases, such as skeletal muscle, liver, and fat, because they represent the metabolic sites which are predominantly responsible for nutrient utilization and storage. One significant discovery is that many metabolic dysfunctions in peripheral tissues are causally related to local inflammation 12, 24, 25, 26, 27, 28, 29, 30. Indeed, evidence derived from epidemiology,
Cellular pathways converging on central NF-κB activation
It is well-established that the NF-κB transcriptional program is a crucial regulator of immunity and inflammation 49, 50, 51. Canonical NF-κB activation is induced predominately by the serine/threonine kinase IKKβ that phosphorylates and degrades IκB proteins, thus liberating NF-κB to enter the nucleus and induce transcription of many inflammatory genes. During the classical immune response and inflammation, IKKβ/NF-κB activation is induced by a number of cell-membrane receptors including TLRs.
Neurodegeneration in obesity and related diseases
The importance of the hypothalamus in regulating body-weight homeostasis was historically shown by lesion studies in animals [86]; indeed, ablation of some ventral hypothalamic regions causes overeating and obesity, whereas disruption of the lateral hypothalamus leads to anorexia and weight loss. However, based on the classical dogma that adult neurons do not undergo turnover, these studies mostly suggested the physiological importance of the hypothalamus, but barely addressed the etiology or
Adult hypothalamic neurogenesis and neural stem cells in mice
It has been known since the 1990s that adult mammalian brains contain multipotent neural stem cells able to generate different neural lineages including neurons, astrocytes, and oligodendrocytes 91, 92. The biological functions of adult neural stem cells might be to mediate adult neurogenesis, a process needed by the brain to maintain its plasticity in response to intrinsic and extrinsic changes [93]. Mammalian adult neural stem cells predominantly exist in the subventricular zone of the
Links between neuroinflammation seen in obesity/T2D and neurodegenerative diseases
Epidemiological and clinical studies suggest that obesity, T2D, and their related lifestyles (e.g., physical inactivity) are highly associated with Alzheimer's diseases and Parkinson's disease 20, 21, 22, 23. Conversely, therapeutic interventions of metabolic diseases have often been shown to protect against neurodegenerative disorders as well 100, 101, suggesting that obesity and diabetes contribute to the development of neural degeneration and neurodegenerative diseases. The potential causal
Concluding remarks
Research during the past decade has demonstrated that obesity and its comorbidities are not only disorders of peripheral tissues but also fundamentally involve neurological changes that result in neural dysregulation and altered metabolic physiology. Recently, interdisciplinary research in neuroscience and immunology has linked overnutrition to IKKβ/NF-κB-directed inflammation in the brain, and particularly in the hypothalamus. This neuroinflammation was shown to impair the neurohormonal as
Acknowledgments
The author sincerely thanks Cai laboratory members for their research relevant to this review; our work in this field has been supported by National Institutes of Health grants (R01 DK078750 and R01 AG031774 to D.C.) and the American Diabetes Association Basic Research Award (#1-12-BS-20 to D.C.). D.C. is an Irma T. Hirschl Scholar.
Glossary
- Hypothalamic inflammation
- diverse types of molecular and cellular changes in the hypothalamus which may differ when responding to different inflammatory stimuli ranging from externally-induced local injuries such as infections, trauma, and stroke to systemic physiological changes such as metabolic abnormalities and aging.
- Metabolic inflammation
- chronic and low-grade inflammatory changes in overnutrition-induced metabolic diseases (such as obesity and T2D) which are displayed primarily in the form
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