ReviewModels and mechanisms for hippocampal dysfunction in obesity and diabetes
Graphical abstract
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.
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