Brain insulin resistance and cognitive function: influence of exercise

Abstract

Exercise has systemic health benefits in people, in part, through improving whole body insulin sensitivity. The brain is an insulin-sensitive organ that is often underdiscussed relative to skeletal muscle, liver, and adipose tissue. Although brain insulin action may have only subtle impacts on peripheral regulation of systemic glucose homeostasis, it is important for weight regulation as well as mental health. In fact, brain insulin signaling is also involved in processes that support healthy cognition. Furthermore, brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer's disease pathology. Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer's dementia.

Keywords: executive function; intranasal insulin; memory; mitochondrial function; physical activity.

Graphical abstract

Figure 1.

A novel mechanism for promoting healthy cognitive function with exercise. Created with BioRender.com with permission. AD, Alzheimer’s disease; ROS, reactive oxygen species.

Figure 2.

Cellular mechanism(s) by which proper peripheral insulin signaling through sedentary lifestyle (A) compared with exercise (B) may impact brain insulin signaling. AKT, serine/threonine protein kinase; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CD36, cluster of differentiation 36; CREB, cAMP response element-binding protein; FFA, free-fatty acids; GLUT1, Glucose transporter type 1; GLUT4, Glucose transporter type 4; GRB2, growth factor receptor bound protein 2; IKK, ikappaB kinase; IL-6, interleukin 6; IL-8, interleukin 8; IRS 1/2, insulin receptor substrate 1/insulin receptor substrate 2; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinases; mTOR, mammalian target of rapamycin; NADH, nicotinamide adenine dinucleotide hydrogen; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; PGC-1α, proliferator-activated receptor-gamma coactivator-1alpha; PI3K, phosphoinositide 3-kinase; PKR, protein kinase R; Ras, guanosine-nucleotide-binding protein; ROS, reactive oxygen species; TNF-α, tumor necrosis factor α; TNFR, tumor necrosis factor receptor; TrKB, tropomyosin receptor kinase B. Created with BioRender with permission.