Spontaneous physical activity and mediators of energy homeostasis in the hypothalamus of mice from 4 to 10 months of age

Abstract

What is the central question of this study? Is the initial decline of spontaneous physical activity (SPA) in mice related to impaired insulin and leptin signalling or brain-derived neurotrophic factor expression in the hypothalamus? What is the main finding and its importance? We showed that SPA started to decline at an early stage, concomitantly with an impairment of hypothalamic leptin signalling. Consequently, energy expenditure decreased and glucose tolerance worsened. Our results demonstrate the need to counteract the initial decline in SPA to avoid metabolic impairments and indicate the possible involvement of central leptin in the reduction in SPA with age. The biological control of physical activity is poorly understood. Age decreases insulin, leptin and brain-derived neurotrophic factor (BDNF) signalling in the hypothalamus, and all have been shown to modulate spontaneous physical activity (SPA). We investigated the age at which SPA starts to decline and whether this is associated with the emergence of hypothalamic insulin and leptin resistance and reduced BDNF expression. Spontaneous physical activity (and other parameters of locomotion) and energy expenditure were determined monthly in mice from the 4th to the 10th month of age. Metabolic and hypothalamic analyses were performed in 4-, 6- and 10-month-old mice. Spontaneous physical activity, distance travelled and speed of locomotion started to decrease in 6-month-old mice. The reduction in SPA became more evident from 8 months of age. Energy expenditure decreased from the 8th month. Hypothalamic BDNF protein expression and insulin signalling did not change throughout the time span studied. Leptin signalling decreased at 6 and 10 months compared with 4 months. Also, compared with 4 months, 6- and 10-month-old mice were glucose intolerant. In conclusion, SPA begins to decline in parallel with reduced hypothalamic leptin signalling. Metabolic impairment also manifests as SPA decreases, highlighting the need to understand the regulation of SPA in order to combat its decline.

CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction

“…During normal ageing, locomotor activity declines with progressive body weight gain [25][26][27], indicating that physical activity is an important health factor [28]. In this regard, laboratory mice have lifelong food availability and generally a sedentary lifestyle.…”

Effects of long-term social isolation on central, behavioural and metabolic parameters in middle-aged mice

“…Here, we investigated the effects of long-term social isolation on metabolic, behavioural, and central nervous system-related areas in middle-aged mice. This is a period of life characterized by the beginning of some age-related metabolic and behavioural alterations [25] , [26] , [27] , [28] , thus being particularly important but yet not so explored. Our main finding was that long-term social isolation can impair short-term memory, which was associated with a decrease in ΔFosB and BDNF expression at hippocampal DG and CA3, respectively.…”

“…Less is known on how long-term social isolation can affect a mature and developed mouse, especially when they reach middle age, a period in which some age-related metabolic and behavioural alterations start to manifest [25] , [26] , [27] . We have shown that middle-aged mice displayed decreased locomotor activity and impaired glucose tolerance [28] , while others have demonstrated a decline in cognitive function as a result of hyperglycemia [29] . Indeed, the decline in cognitive parameters during aging can be explained by an increase in oxidative stress [30] and a decrease in neurotrophins, like brain-derived neurotrophic factor (BDNF) [31] .…”

“…After 6 hours of fasting, blood was collected from the tip of the tail to assess blood glucose, using Accu-Check Advantage II. This protocol ensures that animals were submitted to the same fasting period [28] .…”

Social isolation is a direct determinant of decreased home‐cage activity in mice: A within‐subjects study using a body‐implantable actimeter

“…For rodents, all activity in a home cage, mostly in the form of locomotion and rearing behaviours, is considered physical activity. To date, some determinants of home‐cage activity have been identified, such as a high‐fat diet (Bjursell et al., 2008; Moretto et al., 2017), calorie restriction (Teske & Kotz, 2009), psychosocial stress (Bartolomucci et al., 2003) and ageing (Benfato et al., 2017). Few studies have investigated how social isolation affects home‐cage activity in rodents, however.…”