The opposing effects of diabetes and running on hippocampal neuroplasticity suggest that peripheral metabolic alterations can impact the brain. Neurons are protected by the blood-brain barrier, but a variety of signals can cross the barrier, including corticosterone, insulin, and glucose, and several different growth factors and cytokines. These peripherally derived signals coordinate central adaptations, bringing central nervous system function in line with overall somatic health.
A number of candidate mechanisms have been proposed for the effects of metabolic perturbations on the brain. By comparing the literature surrounding the regulation of brain function by caloric deficit and excess, it is possible to identify common factors that may mediate these opposing effects. The neurotrophin BDNF has been recognized as a potent modulator of neuronal excitability, synaptic function, and hippocampal morphology for over ten years. Levels of BDNF are increased by exercise and caloric restriction (Lee et al., 2002
; Neeper et al., 1995
), and reduced in animal models of diet-induced obesity (Molteni et al., 2002
). Although BDNF also regulates energy intake, pair-feeding experiments following central administration of BDNF in insulin resistant mice indicate that effects on energy metabolism are independent of effects on energy intake (Nakagawa et al., 2000
). BDNF heterozygous knockout mice are obese and insulin resistant (Duan et al., 2003
), but both their diabetes and brain BDNF levels can be normalized by dietary energy restriction suggesting a functional connection between central BDNF levels and peripheral energy metabolism.
Central elevations in corticosterone suppress neuronal glucose metabolism (Sapolsky 1986
), while BDNF and other neurotrophic factors exert the opposite effect (Burkhalter et al., 2003
; Yeo et al., 2004
). This opens the possibility that one mechanism underlying the lack of any negative consequences of exposure to running-induced elevations in corticosterone may involve neurotrophic factors. We and others have observed increases in hippocampal BDNF levels with running (Cotman, Berchtold, and Christie 2007
); in fact, running has previously been demonstrated to protect against the stress-induced downregulation of BDNF (Adlard and Cotman 2004
). These findings suggest that runners may be protected from the deleterious effects of exposure to elevated corticosterone levels through increases in BDNF. However, the effects of running on BDNF are likely to be secondary to changes in levels of another growth factor, insulin-like growth factor 1 (IGF-1).
Insulin-like growth factor (IGF-1) is produced in a variety of organs, including the liver, muscle, and brain (Dore, Kar, and Quirion 1997
). Serum IGF-1 is reduced in animal models of insulin-deficient and insulin-resistant diabetes (Kim et al., 2006
; Kumari et al., 2007
); in contrast, running and caloric restriction both enhance production of IGF-1 (Niedernhofer et al., 2006
; Carro et al., 2001
). A causal relationship for running-induced alterations in serum IGF-1 and hippocampal neurogenesis was proposed, based on experiments using peripheral blockade of IGF-1 (Trejo, Carro, and Torres-Aleman 2001
). Administration of exogenous IGF-1 ameliorates cognitive deficits in diabetic animals, and enhances hippocampal learning in non-diabetic animals (Lupien, Bluhm, and Ishii 2003
). Additionally, the effects of running on hippocampal BDNF levels are prevented when peripheral upregulation of IGF-1 is blocked (Chen and Russo-Neustadt 2007
). Thus, it is possible that alterations in IGF-1 may be upstream of BDNF in the opposing effects of caloric excess and deficit in the hippocampus.