Elsevier

Neuroscience

Volume 309, 19 November 2015, Pages 125-139
Neuroscience

Review
Models and mechanisms for hippocampal dysfunction in obesity and diabetes

https://doi.org/10.1016/j.neuroscience.2015.04.045Get rights and content

Highlights

  • Evidence from human neuroimaging studies indicates that obesity and Type 2 diabetes impair brain structure and function.

  • Neurological changes that occur in metabolic pathologies are not restricted to brain regions involved in metabolism.

  • Research in rodent models of diabetes and obesity has begun to examine synaptic mechanisms for memory impairment.

  • Neuroimmune and neuroendocrine systems mediate hippocampal dysfunction in obesity and diabetes.

Abstract

Clinical studies suggest that obesity and Type 2 (insulin-resistant) diabetes impair the structural integrity of medial temporal lobe regions involved in memory and confer greater vulnerability to neurological insults. While eliminating obesity and its endocrine comorbidities would be the most straightforward way to minimize cognitive risk, structural barriers to physical activity and the widespread availability of calorically dense, highly palatable foods will likely necessitate additional strategies to maintain brain health over the lifespan. Research in rodents has identified numerous correlates of hippocampal functional impairment in obesity and diabetes, with several studies demonstrating causality in subsequent mechanistic studies. This review highlights recent work on pathways and cell–cell interactions underlying the synaptic consequences of obesity, diabetes, or in models with both pathological conditions. Although the mechanisms vary across different animal models, immune activation has emerged as a shared feature of obesity and diabetes, with synergistic exacerbation of neuroinflammation in model systems with both conditions. This review discusses these findings with reference to the benefits of incorporating existing models from the fields of obesity and metabolic disease. Many transgenic lines with basal metabolic alterations or differential susceptibility to diet-induced obesity have yet to be characterized with respect to their cognitive and synaptic phenotype. Adopting these models, and building on the extensive knowledge base used to generate them, is a promising avenue for understanding interactions between peripheral disease states and neurodegenerative disorders.

Introduction

Understanding relationships between cellular metabolism and circuit function is a central question for both basic and clinical neuroscience. Changes in energy intake and expenditure influence synaptic plasticity, and this relationship is not exclusive to brain regions classically implicated in food intake and metabolism. Decades of research in animal models have revealed correlations between metabolic efficiency at the systems level and neuroplasticity in the hippocampus and other regions involved in learning and memory (Bedford et al., 1979, Greenwood and Winocur, 1990, Dulloo and Calokatisa, 1991, Neeper et al., 1995). These relationships are considered bidirectional based on studies demonstrating enhancement of hippocampal plasticity with exercise and caloric restriction (van Praag et al., 1999; Fontán-Lozano et al., 2007), and functional impairment in obesity and diabetes (Magariños and McEwen, 2000, Molteni et al., 2002). Associations between metabolism and neuroplasticity are detectable at the systems level and the cellular level, where insulin receptor activation (Lee et al., 2011), glucose transporter expression and localization (Ferreira et al., 2011), and mitochondrial function (Cheng et al., 2012) have all been linked with synaptic mechanisms for learning and memory. Given the substantial metabolic demands required for synaptic transmission, it is perhaps unsurprising that bidirectional regulation of neuroplasticity by energetic challenges would be evident across most, if not all, brain circuits (for review, see Stranahan and Mattson, 2011). The challenge in addressing this question lies in isolating individual systems impacted by complex pathologies, such as obesity and diabetes.

Nearly 15 years since the first report of increases in dementia risk among diabetics in the Rotterdam study (Ott et al., 1996), obesity and diabetes have yet to be clinically implemented as risk factors for cognitive impairment and dementia. Consequentially, there have been no efforts to develop therapeutics to reduce dementia risk in individuals with diabetes and obesity, and the promise of greater efficacy based on treatments tailored to individual risk factors has yet to be realized. Some of the impediments to translation are likely attributable to variability in the degree to which different animal models of diabetes and obesity mimic features of these conditions in human populations. Type 1 (insulin-deficient) diabetes is typically diagnosed early in life and the most frequent cause is autoimmune destruction of the insulin-producing pancreatic beta cells (Hamman et al., 2014). Type 1 diabetics are not typically overweight or obese, and with adherence to an insulin administration regimen, there is little to no cognitive risk in later life (Lobnig et al., 2006). Type 2 (insulin-resistant) diabetes is a progressive disease, with the earliest stages characterized by elevated fasting glucose levels and compensatory increases in insulin production (American Diabetes Association, 2014). Over time, the pancreatic beta cells become exhausted and the patient converts from insulin-resistant to insulin-deficient diabetes (American Diabetes Association, 2014). Individuals with Type 2 diabetes are frequently, but not always, overweight or obese (Sullivan et al., 2005), and dementia risk is elevated in Type 2 diabetes independent of body mass index (BMI; Xu et al., 2009).

Obesity is a complex disorder that occurs as a consequence of genetic and lifestyle factors (Ogden et al., 2014). While some obese individuals do not develop insulin-resistant diabetes, data from twin studies and longitudinal studies indicate that, even in the absence of metabolic and cardiovascular comorbidities, obesity increases risk for multiple forms of dementia, including vascular dementia and Alzheimer’s disease (AD) (Whitmer et al., 2007, Xu et al., 2011). These reports are consistent with other studies that came to similar conclusions using statistical methods to separate the effects of obesity from those of diabetes (Profenno et al., 2010).

The goal of identifying cellular and systems-level mechanisms for changes in synaptic plasticity and cognition in obesity and diabetes would be significantly advanced by incorporating sophisticated model systems developed in the field of obesity and metabolism. These models include transgenic mice with vulnerability or resistance to the metabolic effects of diet-induced obesity and surgical approaches for manipulating the amount and distribution of adipose tissue. Comparing learning and plasticity measures across model systems with selective deficits in glycemic control or body weight homeostasis could distinguish the effects of diabetes from those of obesity. This approach would enable subsequent studies of synergy between the two conditions and may also assist in refinement of risk criteria in clinical populations. This review highlights recent developments in the literature on mechanisms for impaired hippocampal neuroplasticity in obesity and diabetes, with reference to the importance of addressing related questions in future studies using metabolic models that have yet to be characterized with respect to their cognitive and synaptic phenotype.

Section snippets

Pharmacological models used to study hippocampal plasticity in obesity and diabetes

Streptozotocin (STZ) is a pancreatic beta-cell toxin injected intravenously or intraperitoneally to create a model of insulin-deficient diabetes (Lenzen, 2008). Either STZ or alloxan, a related nitrosylurea compound, causes rapid-onset insulin-deficient diabetes that is accompanied by reductions in body weight in some, but not all studies (Biessels et al., 1998, Magariños and McEwen, 2000, Stranahan et al., 2008a). Studies of hippocampal plasticity in diabetes make frequent use of STZ as a

Non-obese models of insulin-resistant diabetes used to study hippocampal plasticity

The Goto–Kakizaki (GK) rat model allows for disambiguation of synaptic regulation by insulin resistance in the absence of obesity. GK rats were generated by artificial selection for impaired glucose tolerance in the Wistar strain (Goto et al., 1976). This strategy produced a polygenic model of spontaneous insulin-resistant diabetes with normal body weight and food intake (Galli et al., 1996). Studies in GK rats have demonstrated impairment of hippocampal function in the water maze paradigm and

Genetic models used to study hippocampal plasticity in obesity and diabetes

A variety of genetic models with obesity and insulin resistance due to loss-of-function mutations in the gene for the satiety hormone leptin or leptin receptors have been used in studies of hippocampal plasticity. Early research in the Zucker rat, in which obesity and Type 2 diabetes arise from lack of functional leptin receptors, yielded mixed results. Some studies reported deficits in spatial learning using the hippocampus-dependent water maze (Li et al., 2002), but others failed to detect

Inducible genetic models used to study hippocampal plasticity in obesity and diabetes

The possibility that leptin receptor deficiency would exert indirect effects on hippocampal plasticity is cumbersome, but it is also supported by an elegant series of studies using lentiviral manipulation of hypothalamic sensitivity to metabolic signals as a strategy to induce obesity and cognitive impairment in rats. Injection of lentiviral vectors carrying insulin receptor antisense (IRAS) into the third ventricle resulted in downregulation of insulin receptors in the hypothalamic arcuate and

Direct effects of insulin on hippocampal plasticity in diabetes

Although the IRAS studies identified insulin-independent synaptic deficits in non-diabetic obesity, there is substantial evidence of insulin signaling as an obligatory participant in hippocampal function. This evidence comes from studies using intrahippocampal insulin infusions in non-obese, non-diabetic animals, and from studies that measure insulin and glucose in awake behaving animals using microdialysis. Pre-training (Moosavi et al., 2006) or post-training (Babri et al., 2007, Stern et al.,

Diabetic hyper- and hypoglycemia: feast or famine

Individuals with Type 1 diabetes that experience severe hypoglycemic episodes develop structural atrophy in medial temporal regions (Hershey et al., 2010). Patients in the early stages of Type 2 diabetes experience prolonged peripheral hyperglycemia during the early stages of the disease (American Diabetes Association, 2014), and non-insulin drug treatments for lowering glucose levels occasionally overshoot the physiological range and produce episodes of hypoglycemia (Melander, 2004). At later

Diet-induced obesity models used to study hippocampal structure and function

Diet-induced obesity models represent the most relevant system for identifying mechanisms likely to generalize across species. However, experimental variables such as diet composition, duration of exposure, age at onset of diet availability, and variability in individual consumption by experimental animals often complicate the design and interpretation of these studies. The types of diets used to generate obesity in rats and mice vary widely, with some groups using commercially available HFDs

Disambiguation of hormonal effects on metabolism and cognition in diabetes

Chronic activation of the hypothalamic–pituitary-adrenal axis (HPA axis) is known to exacerbate hyperglycemia and insulin resistance in Type 2 diabetes, based on case reports of improved glycemic control following unilateral adrenalectomy in patients with Type 2 diabetes and adrenal tumors (Blüher et al., 2000, Wiesner et al., 2003). Adrenalectomy attenuates hyperglycemia and insulin resistance and completely reverses obesity in db/db mice (Shimomura et al., 1987, Stranahan et al., 2008a). The

Neuroimmune regulation of hippocampal function in obesity

Obesity causes chronic, low-grade inflammation (Kanneganti and Dixit, 2012). During the initial phases of adipose tissue hypertrophy, adipocytes synthesize and release cytokines that attract macrophages (Osborn and Olefsky, 2012). Cytokine production in adipose tissues occurs in a regionally specific manner, with visceral white adipose tissue (vWAT) as the predominant driver of inflammation in obesity (Rosen and Spiegelman, 2014). The role of adipose tissue inflammation in the metabolic

Metabolic models of differential adiposity and resistance to dietary obesity: the next frontier

Obesity and insulin-resistant diabetes each evoke a series of signaling cascades leading to impaired hippocampal function, with mechanistic overlap at multiple levels both within and outside the central nervous system. However, closer examination of the pathological features of obesity and diabetes reveals elements of each disease that can be separately examined using existing animal models (Fig. 2). In obesity, the metabolic consequences of increased adiposity depend on the distribution of

Conclusion

Patterns consistent with enhanced synaptic function with exercise or caloric restriction, and maladaptive plasticity with obesity or diabetes, are evident in the cerebellum (Sickmann et al., 2010, Green et al., 2011), brainstem (Landsberg, 2006, Michelini and Stern, 2009), hypothalamus (Horvath, 2005, Stranahan et al., 2012b), hippocampus (Neeper et al., 1995; Fontán-Lozano et al., 2007; Stranahan et al., 2008a), and across multiple cortical areas (Ehninger and Kempermann, 2003, Stranahan et

Acknowledgments

This work was supported by grants (K01DK100616 and R03DK101817) from the National Institutes of Health.

References (149)

  • C.W. Cotman et al.

    Exercise builds brain health: key roles of growth factor cascades and inflammation

    Trends Neurosci

    (2007)
  • A. Dey et al.

    Glucocorticoid sensitization of microglia in a genetic mouse model of obesity and diabetes

    J Neuroimmunol

    (2014)
  • M.G. Frank et al.

    Rapid isolation of highly enriched and quiescent microglia from adult rat hippocampus: immunophenotypic and functional characteristics

    J Neurosci Methods

    (2006)
  • M.G. Frank et al.

    Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses

    Brain Behav Immun

    (2012)
  • J.T. Green et al.

    The effects of two forms of physical activity on eyeblink classical conditioning

    Behav Brain Res

    (2011)
  • C.E. Greenwood et al.

    Learning and memory impairment in rats fed a high saturated fat diet

    Behav Neural Biol

    (1990)
  • C.A. Grillo et al.

    Lentivirus-mediated downregulation of hypothalamic insulin receptor expression

    Physiol Behav

    (2007)
  • C.A. Grillo et al.

    Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent

    Brain Res

    (2009)
  • C.A. Grillo et al.

    Obesity/hyperleptinemic phenotype impairs structural and functional plasticity in the rat hippocampus

    Physiol Behav

    (2011)
  • C.A. Grillo et al.

    Obesity/hyperleptinemic phenotype adversely affects hippocampal plasticity: effects of dietary restriction

    Physiol Behav

    (2011)
  • C.A. Grillo et al.

    Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats

    Behav Brain Res

    (2011)
  • B.T. Lang et al.

    Impaired neurogenesis in adult type-2 diabetic rats

    Brain Res

    (2009)
  • C.C. Lee et al.

    Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways

    Neuropharmacology

    (2011)
  • X.L. Li et al.

    Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents

    Neuroscience

    (2002)
  • J.S. Marino et al.

    Central insulin and leptin-mediated autonomic control of glucose homeostasis

    Trends Endocrinol Metab

    (2011)
  • M.M. Mauer et al.

    The regulation of total body fat: lessons learned from lipectomy studies

    Neurosci Biobehav Rev

    (2001)
  • E.C. McNay et al.

    Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance

    Neurobiol Learn Mem

    (2010)
  • R. Molteni et al.

    A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning

    Neuroscience

    (2002)
  • A. Montagne et al.

    Blood–brain barrier breakdown in the aging human hippocampus

    Neuron

    (2015)
  • M. Moosavi et al.

    The effect of intrahippocampal insulin microinjection on spatial learning and memory

    Horm Behav

    (2006)
  • N.J. Abbott et al.

    Astrocyte–endothelial interactions at the blood–brain barrier

    Nat Rev Neurosci

    (2006)
  • S.F. Akana et al.

    Corticosterone exerts site-specific and state-dependent effects in prefrontal cortex and amygdala on regulation of adrenocorticotropic hormone, insulin and fat depots

    J Neuroendocrinol

    (2001)
  • American Diabetes Association

    Diagnosis and classification of diabetes mellitus

    Diabetes Care

    (2014)
  • J. Audoy-Rémus et al.

    Rod-Shaped monocytes patrol the brain vasculature and give rise to perivascular macrophages under the influence of proinflammatory cytokines and angiopoietin-2

    J Neurosci

    (2008)
  • H.E. Auvinen et al.

    The effects of high fat diet on the basal activity of the hypothalamus-pituitary-adrenal axis in mice

    J Endocrinol

    (2012)
  • W.A. Banks et al.

    Transport of insulin across the blood–brain barrier: saturability at euglycemic doses of insulin

    Peptides

    (1987)
  • S.A. Beddow et al.

    Fasting hyperglycemia in the Goto-Kakizaki rat is dependent on corticosterone: a confounding variable in rodent models of type 2 diabetes

    Dis Model Mech

    (2012)
  • T.G. Bedford et al.

    Maximum oxygen consumption of rats and its changes with various experimental procedures

    J Appl Physiol

    (1979)
  • M. Blüher et al.

    Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma

    Diabetes Care

    (2000)
  • S.G. Bouret et al.

    Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits

    J Neurosci

    (2012)
  • O. Butovsky et al.

    Identification of a unique TGF-β-dependent molecular and functional signature in microglia

    Nat Neurosci

    (2014)
  • J.L. Chan et al.

    Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess

    J Clin Endocrinol Metab

    (2005)
  • J.L. Chan et al.

    Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans

    Proc Natl Acad Sci U S A

    (2006)
  • A. Cheng et al.

    Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines

    Nat Commun

    (2012)
  • J.P. Després et al.

    Abdominal obesity and metabolic syndrome

    Nature

    (2006)
  • J.C. Diegues et al.

    Spatial memory in sedentary and trained diabetic rats: molecular mechanisms

    Hippocampus

    (2014)
  • A.L. Dinel et al.

    Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome

    PLoS One

    (2011)
  • A.G. Dulloo et al.

    Adaptation to low calorie intake in obese mice: contribution of a metabolic component to diminished energy expenditures during and after weight loss

    Int J Obes

    (1991)
  • D. Ehninger et al.

    Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex

    Cereb Cortex

    (2003)
  • J.R. Erion et al.

    Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity

    J Neurosci

    (2014)
  • Cited by (84)

    • Thromboxane A2 synthase inhibition ameliorates endothelial dysfunction, memory deficits, oxidative stress and neuroinflammation in rat model of streptozotocin diabetes induced dementia

      2021, Physiology and Behavior
      Citation Excerpt :

      STZ further documented to produce a marked rise in reactive oxygen species [79]; decrease in antioxidant levels (Bassani et al., 2018); induce cognitive dysfunction and neurodegeneration [58, 59, 82] in rats Therefore, above mentioned changes in STZ rats are in consonance with the previous studies. Moreover noted decline in body weight of STZ rats is also in line with the earlier report [63](Stranahan AM, 2015). It has been further reported that STZ induced diabetes does not affect the locomotor activity of the rats [77] .

    • Altered neural correlates of episodic memory in adolescents with severe obesity

      2019, Developmental Cognitive Neuroscience
      Citation Excerpt :

      Animal studies suggest that the MTL may be more vulnerable to systemic and metabolic pathology associated with obesity due to its high potential for plasticity. In particular, obesity is associated with chronic, low-grade systemic inflammation, which contributes to elevated neuroinflammation (Miller and Spencer, 2014; Spyridaki et al., 2016) that is thought to be a primary mechanism for hippocampal dysfunction associated with obesity (Stranahan, 2015). Exposure to “Western Diets”, marked by high levels of saturated fats and sugar, has been shown to result in increased hippocampal cell death, with long-term exposure resulting in impaired long-term potentiation, a form of synaptic plasticity subserving learning and memory (Hargrave et al., 2016).

    View all citing articles on Scopus
    View full text