The Neuropsychiatric Consequences of Obesity
Metabolism and Memory:
Obesity, Diabetes, and Dementia
The neuropsychiatric consequences of obesity have narrowly focused on cerebrovascular diseases, such as stroke, and the psychological consequences of stigma. However, large-scale studies showing an association between obesity, diabetes, and dementia indicate that the brain is more broadly impacted.
The dementia-obesity-diabetes connection is part of an evolving story forcing us to re-examine a long-standing conceptualization of the mind and the body as separate. When Rene Descartes famously wrote about mind-body dualism in the 17th century, he was reformulating ideas that were ancient even to him. It is now understood that cognition, affect, memory, and other mental processes are manifestations of the brain’s function. Although contemporary neuroscience has largely dismantled Descartes’ dichotomy, brain-body dualism continues to exist, as evidenced by virtually separate health care systems dedicated to mental and physical health.
This has important implications for the way we approach seemingly disparate, difficult-to-treat physical and mental disorders. The relationship between diabetes and dementia is the perfect example. Applying an ethos of brain-body dualism to this problem suggests that it is up to internists and endocrinologists to tackle obesity and diabetes, while psychiatrists and neurologists deal with neurocognitive disorders. However, a scientific understanding of these disorders suggests that breaking down these silos may lead to important pathologic and therapeutic discoveries.
So how does obesity or diabetes contribute to a 50% increase in the risk of dementia? What is the connection between weight, metabolism, and brain health? A key link may be the impact of inflammation and oxidative stress on the brain.
Decades of study on a wide range of diseases including cancer and heart disease have demonstrated that inflammation and oxidative stress play major roles in human pathology. Many of the same processes that affect coronary arteries and visceral organs also impact the brain. Inflammation leads to
Both diabetes and obesity increase inflammation systemically. Until recently, the blood-brain barrier (BBB) was thought to protect the brain from such systemic effects. We now know that the brain is significantly impacted by the inflammatory state of obesity/diabetes through several pathways. First, many of the systemic inflammatory mediators—cytokines, for example—actually do cross the BBB under certain conditions. Second, metabolic mediators released by adipose tissue and the pancreas—leptin, insulin, and amylin—have additional important roles in mediating central nervous system (CNS) inflammation and regulating neuronal health. Parsing some of the details of what exactly happens to the brain in diabetes and obesity may provide new targets for dementia treatments.
While often thought of as inert, we now realize that fat itself may play a major role in regulating cognitive health. Adipose tissue serves a range of neuroendocrine functions. One of the most important functions is the production and release of an array of polypeptides dubbed adipokines. These have a wide range of effects, from modulating metabolism (through leptin), mediating blood clotting (via plasminogen activation inhibitors), and regulating the inflammatory pathway (including via interleukins and tumor necrosis factors). In metabolically healthy people, adipokine secretion is tailored to physiologic need. However, in obesity, the adipokine environment enters a state sometimes known as
Research shows that the pathologic changes of
As inflammation damages structures responsible for learning, memory, and cognition, the positive neurocognitive effects of leptin are diminished.
Leptin is best known for regulating satiety and energy intake. However, it also promotes axonal growth and enhances long-term potentiation through modulation of N-methyl-D-aspartate function. These characteristics suggest its importance in memory and learning. Obesity states are associated with leptin resistance. Resistance to the effects of leptin is not limited to its ability to regulate eating—it may also dull leptin’s role in cognitive enhancement.
As with adipose tissue, pancreatic peptides also have important roles in the brain. While insulin is best known for its role in cellular glucose intake, research into its role in cognition is gaining momentum. Insulin receptors are involved in learning and memory, with high concentrations of receptors in the cortex and the hippocampus. In addition, insulin (and insulin-like growth factor 1) act as neurotrophic factors that promote synaptic plasticity.
In type 2 diabetes, the body becomes resistant to insulin, forcing the pancreas to produce increasingly large quantities of insulin to promote glucose uptake by cells. As is the case with leptin, systemic insulin resistance blunts the procognitive effects of insulin in the brain: insulin resistance is associated with decreased verbal fluency, low gray matter volume in the temporal lobes, and declarative memory impairments. What’s more, insulin transport into the brain may be downregulated by peripheral insulin resistance, and this can affect glucose metabolism in the CNS, contribute to oxidative stress, and inhibit insulin’s neurotrophic effects.
At the same time, because the absolute quantities of insulin are increasingly elevated (although the effect is lessened), hyperinsulinemia leads to the formation of peripheral and central amyloid-β plaques similar to those seen in the neuropathology of Alzheimer’s disease and other neurodegenerative disorders. These plaques may activate inflammation in the CNS, leading to further neuronal death and plaque formation.
Yet another piece of the story may come from amylin, a hormone produced primarily by the pancreas. Like leptin, amylin functions to
Thinking across the
Even within the relatively isolated problem of the obesity-diabetes-dementia connection, there are a dizzying number of interrelated but distinct pathways knotted together. However, within that knot lies potential solutions to health problems that have a massive human cost. Imagine if we could prevent Alzheimer’s disease with weight and metabolic management? Or if obesity and diabetes treatments could help protect the brains of people with early cognitive disorders? These ideas may not be so far-fetched. Although still in the first stages of
Larger and more robust trials are underway to determine whether treating dementia with intranasal insulin may be a viable therapeutic strategy. And so many other health problems may lend themselves to rethinking along similar lines: the link between depression and inflammation and the role of the gut microbiome in psychiatry are two examples.
These problems are remarkably complex; effectively addressing them will require integrated approaches to research and clinical care. Such approaches hold the potential to revolutionize the tools we can offer our patients to improve their health—body and brain alike.
Biological Psychiatry, Volume 82, Issue 11, 1 December 2017, Pages 828-838 https://doi.org/10.1016/j.biopsych.2017.09.025
Ogden CL, Carroll MD, Kit BK, Flegal KM (2012): Prevalence of obesity in the United States, 2009-2010. Available at: https://www.cdc.gov/nchs/data/databriefs/db82.pdf. Accessed September 21, 2017.
Pedditizi, R. Peters, N. Beckett The risk of overweight/obesity in mid-life and late lifefor the development of dementia: A systematic review and meta-analysis of longitudinal studies Age Ageing, 45 (2016), pp. 14-21 CrossRefView Record in Scopus
Zhang, C. Chen, S. Hua, H. Liao, M. Wang, Y. Xiong, F. Cao An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer’s disease Diabetes Res Clin Pract, 124 (2017), pp. 41-47 ArticleDownload PDFCrossRefView Record in Scopus
M. Walker, F.E. Harrison Shared neuropathological characteristics of obesity, type 2 diabetes
andAlzheimer’s disease: Impacts on cognitive decline Nutrients, 7 (2015), pp. 7332-7357 CrossRefView Record in Scopus
J. Kiliaan, I.A.C. Arnoldussen, D.R. Gustafson Adipokines: A link between obesity and dementia? Lancet Neurol, 13 (2014), pp. 913-923 ArticleDownload PDFView Record in Scopus
Parimisetty, A.C. Dorsemans, R. Awada, P. Ravanan, N. Diotel, C. Lefebvre d’Hellencourt Secret talk between adipose tissue and central nervous system via secreted factors—an emerging frontier in the neurodegenerative research J Neuroinflammation, 13 (2016), p. 67
A.C. Arnoldussen, A.J. Kiliaan, D.R. Gustafson Obesity
anddementia: Adipokines interact with the brain Eur Neuropsychopharmacol, 24 (2014), pp. 1982-1999 ArticleDownload PDFView Record in Scopus
J. Reiner, E.G. Mietlicki-Baase, D.R. Olivos, L.E. McGrath, D.J. Zimmer, K. Koch-Laskowski, et al. Amylin acts in the lateral dorsal tegmental nucleus to regulate energy balance through gamma-aminobutyric acid signaling Biol Psychiatry, 82 (2017), pp. 828-838 ArticleDownload PDFView Record in Scopus
Q. Qiu, R. Au, H. Zhu, M. Wallack, E. Liebson, H. Li, et al. Positive association between plasma amylin and cognition in a homebound elderly population J Alzheimers Dis, 42 (2014), pp. 555-563 View Record in Scopus
A. Lutz, U. Meyer Amylin at the interface between metabolic and neurodegenerative disorders Front Neurosci, 9 (2015), p. 216 CrossRef
© 2017 Society of Biological Psychiatry.