Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care

Abstract

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.

Keywords: circadian clock; diet; environment; exercise; genetics; inflammation; metabolism; personalized medicine; thermal regulation; treatment.

Figure 1

Gene-environment interactions regulating disease risk of obesity and type 2 diabetes Individual genetic predispositions and environmental factors interact to promote or impair molecular processes, such as circadian regulation, thermal tolerance, and/or chronic inflammation. Accumulation of genetic and environment risk factors eventually leads to the development of complications, reducing both healthspan and lifespan.

Figure 2

Genetic prediction of body weight—context matters A 49-year old woman, who eats a balanced diet, runs 6 miles/day, and commutes by bike to work, does a direct-to-consumer genetic test with one of the many online personalized genomics companies. The company claims to provide genetic insight into her health to make it easier for her to take action. She provides a saliva sample and completes numerous questionnaires on her physical and mental health, family medical history, and more. Her reported results show that, based on the genetic variants tested, she carries 376 weight-lowering variants and 332 weight-increasing variants, predisposing her to weigh about “average” or 157 lbs (71.2 kg, based on the company’s customers’ weight of the same age, height, and sex). However, the woman’s real weight was 120 lbs (54.4 kg). A likely reason for why this genetic test overpredicted the woman’s weight by 30% is because her lifestyle—even though information was shared in detail—was not appropriately incorporated in the prediction models.

Figure 3

Epigenetic modifications in response to environmental factors lead to transgenerational effects on the phenotypes of offspring Diet and exercise influence the cellular availability of nutrients impacting methylation, acetylation and phosphorylation of chromatin. Paternal or maternal environmental exposure can therefore influence metabolism and manifest obesity- or type 2 diabetes-related traits in the offspring through transgenerational epigenetic inheritance.

Figure 4

Circadian control and influence of energy sensing pathways Mitochondrial function, substrate utilization, insulin sensitivity, and glycemic control exhibit diurnal rhythms that are influenced by a variety of factors including energetic stressors such as diet, exercise, and metabolic disease, as well as intrinsic clocks. The molecular circadian clock is composed of transcriptional activators, circadian locomotor output cycles kaput (CLOCK), and brain and muscle ARNTL-like protein 1 (BMAL1), and their target genes period (PER), cryptochrome (CRY), NR1D1 (which encodes REV-ERBα) and DBP, which rhythmically accumulate and form a repressor complex that interacts with CLOCK and BMAL1 to inhibit transcriptional activity. Energetic stressors influence the circadian program and metabolism. AMPK-mediated phosphorylation of CRY and PER promotes their destabilization and degradation, while mTOR activation induces CRY1 expression. PER2 inhibits mTOR complex activity via the tuberous sclerosis complex 1. HIF1α regulates PER2 transcription and interacts with BMAL1 at the chromatin level. CRY1 reduces HIF1α half-life by interacting with its basic-helix-loop-helix domain.

Figure 5

Beneficial effects of exercise training on metabolic risk Decreased thermal tolerance, increased chronic inflammation, deregulated circadian rhythms, and poor glucose control worsen with age and disease development, increasing the susceptibility to life-threatening infections and extreme temperatures and eventually the risk of cardiovascular events (CVD). Exercise triggers acute and transient changes in inflammation and body temperature. These acute events are required for the beneficial effects of exercise training. Exercise training slows the progression of chronic inflammation, limits the decrease in heat-tolerance, and helps synchronize circadian clocks, thereby improving metabolism.