Chowing down:diet considerations in rodent models of metabolic disease

Diet plays a substantial role in the etiology, progression, and treatment of chronic disease and is best considered as a multifacetedset of modifiable input variables with pleiotropic effects on a variety of biological pathways spanning multiple organ systems. Thisbrief review discusses key issues related to the design and conduct of diet interventions in rodent models of metabolic disease andtheir implications for interpreting experiments. We also make specific recommendations to improve rodent diet studies to help betterunderstand the role of diet on metabolic physiology and thereby improve our understanding of metabolic disease.

Obesity:an evolutionary context

People completely lacking body fat(lipodystrophy/lipoatrophy)and those with severe obesity both show profound metabolic and other health issues.Regulating levels of body fat somewhere between these limits would,therefore,appear to be adaptive.Two different models might be contemplated.More traditional is a set point(SP)where the levels are regulated around a fixed level.Alternatively,dual-intervention point(DIP)is a system that tolerates fairly wide variation but is activated when critically high or low levels are breached.The DIP system seems to fit our experience much better than an SP,and models suggest that it is more likely to have evolved.A DIP system may have evolved because of two contrasting selection pressures.At the lower end,we may have been selected to avoid low levels of fat as a buffer against starvation,to avoid disease-induced anorexia,and to support reproduction.At the upper end,we may have been selected to avoid excess storage because of the elevated risks of predation.This upper limit of control seems to have malfunctioned because some of us deposit large fat stores,with important negative health effects.Why has evolution not protected us against this problem?One possibility is that the protective system slowly fell apart due to random mutations after we dramatically reduced the risk of being predated during our evolutionary history.By chance,it fell apart more in some people than others,and these people are now unable to effectively manage their weight in the face of the modern food glut.To understand the evolutionary context of obesity,it is important to separate the adaptive reason for storing some fat(i.e.the lower intervention point),from the nonadaptive reason for storing lots of fat(a broken upper intervention point).The DIP model has several consequences,showing how we understand the obesity problem and what happens when we attempt to treat it.

Effect of disrupted episodic memory on food consumption:no impact of neuronal loss of endophilin A1 on food intake and energy balance

Food intake is generally assumed to reflect a regulatory tension between homeostatic and hedonic drivers.Information from individuals with memory dysfunction suggests that episodic memory may also play a significant role.We reasoned that if memory influences food intake,then disrupting a genetic factor that is important in episodic memory formation should affect food intake and energy balance.We performed spatial learning tests on neuronal specific endophilin A1(EENA1)KO mice using the four-arm baited version of the radial arms maze(RAM).Energy regulation has also been evaluated.As anticipated neuronal EENA1 KO mice had impaired spatial memory.However,loss of endophilin A1 did not result in greater food intake,or altered energy absorption efficiency,relative to wild-type(WT)mice,when fed either low or high fat diets.Moreover,loss of EENA1 did not significantly affect other features of energy balance—physical activity and energy expenditure.No statistically significant changes were observed in the expression of hypothalamic neuropeptides related to food intake regulation,or circulating levels of leptin.We conclude that food intake and energy balance are largely governed by homeostatic and hedonic processes,and when these processes are intact memory probably plays a relatively minor role in food intake regulation.

Using Doubly-Labeled Water to Measure Energy Expenditure in an Important Small Ectotherm Drosophila melanogaster

Energy expenditure is a key variable in the study of ageing, and the fruit fly Drosophila melanogaster is a model organism that has been used to make step changes in our understanding of the ageing process. Standard methods for measurement of energy expenditure involve placing individuals in metabolic chambers where their oxygen consumption and CO2 production can be quantified. These measurements require separating individuals from any social context, and may only poorly reflect the environment in which the animals normally live. The doubly-labeled water （DLW） method is an isotope-based technique for measuring energy expenditure which overcomes these problems. However, technical challenges mean that the smallest animals this method has been previously applied to weighed 50-200 mg. We overcame these technical challenges to measure energy demands in Drosophila weighing 0.78 mg. Mass-specific energy expenditure varied between 43 and 65 mW·g^-1. These estimates are considerably higher than estimates using indirect calorimetry of Drosophila in small metabolic chambers （around 18 mW·g^-1）. The methodology we have established extends downwards by three orders of magnitude the size of animals that can be measured using DLW. This approach may be of considerable value in future ageing research attempting to understand the genetic and genomic basis of ageing.

Targeting Ageing to Decrease Complex Non-Communicable Human Diseases

During the last two centuries, there have been many spectacular advances in medical science, the main consequence of which has been the dramatically reduced burden of infectious diseases. While in the 1800s many people died before reaching adult- hood, nowadays most people survive. Hence average life ex- pectancy in 1800s was around 30-40, which was barely higher than it had been in Greek and Roman times （Finch, 2010）, but nowadays life expectancy in most modernised economies is around 75 - 80. This demographic shift, which has happened in only 200 years, has created a dramatic change in the causes of mortality. The major killers in the modern world are non- communicable diseases （NCDs）： principally cardiovascular disease, cancer and neurodegenerative disorders such as Alz- heimer＇s disease. A major factor that influences susceptibility to all these diseases is age. As we get older, our risk of developing these NCDs increases enormously. For example, the rate of breast cancer in females at age 15-19 is less than 10 per 100,000 population, but this increases to 100 at age 40-44, 275 at age 55--59 and 450 at age 85 ＋ （http：//www.cancerresearchuk.org/ cancer-info/cancerstats/types/breast/incidence/#age）. Ageing has consequently become a major medical, social and economic burden to many countries.