By Emma Pettengale, Commissioning Editor, Portland Press
According to the World Health Organisation, as of 2014 over 600 million adults worldwide are obese, with obesity posing a significant risk to individuals for diseases such as diabetes, cardiovascular disease, osteoarthritis and some cancers.
It’s not just about how much you eat and exercise, molecular factors play a part – the genes you inherited from your parents might pre-dispose you to have an increased risk of obesity, interactions between the environment and your genes have a role and energy balance is not a simple equation.
Standard models of weight gain tend to oversimplify the balance between energy intake (food) and energy expenditure (exercise), and do not take into account the potential for our bodies to restore energy homoeostasis during periods of energy deficit or surplus. Our bodies are not static systems and while there is a relationship between energy intake and expenditure, there is significant variability between individuals in our ability to compensate – partially explaining why there is such high variability in diet-and-exercise-focused-weight-loss plans.
Regulation of energy balance is a dynamic process, with many complex molecular mechanisms. These include the regulation of gene expression, complex interactions between neural regulatory signals and multiple feedback signals arising from areas of the body such as the gastrointestinal tract, as well as interactions with environmental factors.
Genetics and epigenetics
Calorie intake and activity level are overwhelmingly the strongest factors when it comes to obesity; however, there are other factors which have also been shown to have a significant role in who becomes obese in an obesity-prone environment, including the gut microbiome, sleep patterns and genetics.
Gene expression is not a fixed constant – genes can be switched on and off – and epigenetics, in particular DNA methylation, is the primary mechanism through which the environment effects gene expression. Obesity-predisposing gene variants interact with the environment, biological factors such as age and sex, and lifestyle factors such as diet and level of physical activity, leading to differing expression levels in different individuals. Epigenome-wide association studies (EWAS) have led to the identification of specific methylation patterns associated with obesity and support an emerging mechanistic model to explain gene–environment interactions in obesity. The following image, shows a biological model proposed to explain gene–environment interactions in obesity, read this recent Clinical Science review if you’d like to know more.
Molecular signals are central to the mechanisms controlling energy homoeostasis, including the ones that regulate our appetites, and the signals involved in avoiding weight-loss are much stronger and more tightly controlled than regulatory signals to prevent overfeeding.
The molecular mechanisms that regulate appetite and tell us when we need to eat play a key role in the development of obesity. Recent studies indicate that these signals are stronger in overweight individuals, indicating that as people become fatter it is harder to control your appetite.
To find out more about the specific molecular signals involved, including leptin signals, adipose tissues, glucose sensing and insulin resistance, cellular energy sensors such as AMP-activated protein kinase and fat-free mass read this recent review in Clinical Science, summarised in the image below.
Our metabolism and immune systems are highly integrated and an altered balance between metabolic and inflammatory signalling may contribute to the pathophysiology of obesity-related diseases. Adipose tissue represents the major organ for energy storage, in the form of lipids or fat, and obesity is not dependent on your weight, but on the amount of body fat or adipose tissue you have.
Weight gain and the accumulation of adipose tissues in the body leads to resistance to insulin signalling, which may link obesity to metabolic diseases such as diabetes. Research has shown a strong link between tissue inflammation and insulin resistance; however, it is not yet clear whether inflammation represents a consequence or a cause of impaired insulin sensitivity. Matthias Blüher explores this conundrum in this recent Clinical Science review.
The development from normal adipose tissue function to adipose tissue inflammation is most likely initiated by a chronically positive energy balance, which causes lipid accumulation and adipocyte hypertrophy. Lipid accumulation and increased adipose tissue leads to increased body fat – and hence weight gain and eventually obesity. The image below summarises some of the potential mechanisms for the development of adipose tissue inflammation.
Further understanding of the role the immune system and inflammation play in adipose tissue expansion and lipid accumulation may offer therapeutic approaches for the prevention of insulin sensitivity and obesity-related metabolic diseases in the future.
Although on one hand weight-gain can be explained by a ‘simple’ imbalance between energy intake and energy expenditure, the mechanisms that drive our appetites, energy storage and expenditure in the prevailing obesogenic environment are tremendously complex.
If we can understand the influence and effect of molecular mechanisms in obesity, we may one day be able to apply this knowledge to determine personalised risk, lifestyle recommendations and therapeutic interventions.