Recent Trends in Obesity-related Research in Medicine
By Dr. In-ae Lee
Düsseldorf, Germany
Obesity is a phenomenon becoming more prevalent around the world that has reached epidemic proportions in Westernized cultures, and the diseases associated with it (including insulin resistance, type II diabetes mellitus, hepatic steatosis, and atherosclerotic cardiovascular diseases) have become major public health problems [1].
Obesity-related research has been conducted on multiple levels, from molecular to socio-environmental, showing that obesity results from the interaction of cellular factors with social factors. Potential biological drivers of obesity include neurobiological mechanisms, epigenetic gene-environment interactions and gut microbiota [2].
Neurohormonal Controls
A complex interplay of neurotransmitters, hormones and metabolites regulates food intake in the brain. Metabolic-sensing neurons respond to signals of energy intake, demand, or storage, including circulating glucose, leptin, insulin, ghrelin, adrenal steroids, polypeptide YY, fatty acids, ketone, lactate, vagal nerve afferents and intrinsic neurotransmitters [3]. In response, hypothalamic neurons release neurotransmitters that activate either catabolic or anabolic processes. For most humans, however, the feedback signals against excess food intake are not sufficient enough to maintain normal body weight when they have easy access to palatable, calorie-dense food[3].
When provided a diet high in calories, animals, prone to obesity, rapidly increase fat stores [4]. Furthermore, when obese rats lose weight they mount the neurohormonal drive to increase intake and decrease energy expenditure, effectively defending obesity [5, 6]. After weight loss, average resting energy expenditure of obese people is markedly and persistently reduced [7]. These factors are blamed for the weight regain that occurs in approximately 80-90% of obese people who have lost weight [7, 8].
Behavioral animal studies have shown that when a palatable and calorie-dense diet is provided, rats eat far beyond limits of homeostasis and develop extreme levels of obesity even among rats predisposed to leanness [9]. The more palatable the diet, the higher the degree of obesity and the longer it is sustained [9].
The stimuli that augment the drive to obtain foods, the so-called “reward properties of food”, are mediated through receptors that also mediate addiction. Metabolic signals modify the sensing thresholds for food-seeking behavior and reward signals [10]. Chronic stress enhances the reward value of foods [11]. Subconscious drives for intake are cortically integrated into learned motivational cues that can drive intake well beyond subcortical demands of energy needs [12].
Neurohormonal mechanisms
Studies have found that shorter sleep times in childhood were significantly associated with increased body mass index [13, 14]. Experimental studies of sleep deprivation show increased hunger and appetite associated with neurohormonal mechanisms that promote food intake. Debate remains about the strength of the evidence that poor sleep causes obesity, as interventions to decrease obesity by increasing sleep have yet to be reported [15].
Distracting stimuli, such as television viewing while eating, strongly increase intake [16]. In a controlled experiment, viewing children’s food advertisements caused children to eat much larger portions of snack foods compared to children who watched nonfood advertisements, and the effect was significantly larger on obese children than on normal-weight children. These advertisements associate fast-food restaurants or sweetened cereals with fun and happiness, seeking to influence the emotional response to foods, and successfully alter the perceived reward value of foods [17, 18].
Epigenetics
The term epigenetics refers to cellular mechanisms that affect gene expression without changing DNA sequence [19]. Epigenetic markings can be inherited and modified throughout the lifespan [20]. Some changes in gene expression persist even across generations [21]. Several animal studies illustrate epigenetic influences on obesity.
The Agouty mouse is a well-described model of epigenetically-controlled obesity. Obesity is developed due to inadequate methylation of the obese allele [21]. Maternal ingestion of bisphenol A, a chemical used in plastic, decreased methylation of the obese allele in the offspring [22]. This decrease in methylation did not occur when a methyl donor, such as folic acid or vitamin B12, was added to the diet containing bisphenol A [22].
Rats whose mothers do not eat enough protein during pregnancy have decreased methylation and have increased insulin resistance, dyslipidemia and hypertension. Giving mothers folic acid supplements prevented the hypomethylation and normalized the gene expression in offspring [23].
Two rare human obesity syndromes, Prader-Willi and Beckwith-Wiedemann, can result from inappropriate methylation of imprinted genes [21].
A recent study of adults who were exposed to well-defined poor nutrition in utero, caused by the Dutch famine of 1944 -1945, showed that adults who were exposed to poor nutrition early in gestational development had an increased prevalence of glucose intolerance, dyslipidemia, early coronary heart disease, and obesity compared with unaffected siblings [24, 25]. This study is reportedly the first to provide empirical support for the hypothesis that environmental exposures can cause epigenetic changes in humans.
If epigenetic modifications that increase risk for obesity occur widely in humans, the implications for public health interventions could be substantial. At present, however, direct evidence in humans is sparse [1].
Gut Microbiota
Microbiological research indicates that the pathogenesis of obesity may be influenced by our endogenous gastrointestinal microbiota. These microbes metabolize otherwise indigestible components of the diet, and the products of microbial metabolism affect the amount of energy absorbed [26].
Two groups of beneficial bacteria are dominant in the human gut – the Bacteroidetes and the Firmicutes. Obese rodents and humans have a significantly lower percentage of Bacteroidetes in their gut microbiome, and an increase in Firmicutes bacteria, compared to their lean counterparts. Weight loss, on a low-calorie diet by obese individuals, corrected this disproportion [26].
Germ-free mice showed a dramatic increase in body fat within 10-14 days after colonization with bacteria from the distal gut of mice that were raised conventionally despite an associated decrease in food consumption [27].
Further studies were conducted using obese mice with homozygotous mutation in the leptin gene (ob/ob) as well their lean littermates (+/+). In the ob/ob mouse model increased food consumption due to genetic leptin deficiency was found to be the primary cause for obesity in these mice.
Comparative metagenomic analysis showed that the percentage of Bacteroidetes in ob/ob mice was lower by 50%, whereas that of Firmicutes was higher by a corresponding degree. These differences were not attributable to differences in food consumption. Analogous differences have been observed in the distal gut microbiota of lean versus obese humans [26]. This result revealed a correlation between host genotype and the gene content of the microbiome.
To determine if microbial community gene content is a potential contributing factor to obesity, lean (+/+) and obese (ob/ob) caecal bacteria were transplanted into germ-free wild-type mouse recipients. Ob/ob recipient microbiota had a significantly higher percentage of Firmicutes, and significantly less energy remaining in their faeces relative to their lean littermates, showing again that the microbiome associated with obesity is more efficient at harvesting dietary energy [26]. Most importantly, mice colonized with an ob/ob microbiota exhibited a significantly greater percentage increase in body fat over two weeks than mice colonized with lean (+/+) microbiota, corresponding to a difference of 2% of total calories consumed [26]. While this may not seem significant, the alteration in efficiency of energy harvest from the diet, produced by changes in gut microbial ecology, does seem to be great to contribute to obesity, given that small changes in energy balance over the course of a year can result in significant changes in body weight.
These results highlight a potentially relevant connection between gut microbial function and endogenous molecular pathways controlling energy balance, with potential therapeutic implications in the future. However, the exact properties in the obese gut that tip the balance towards the Firmicutes are still unclear.
A recent case-control study found that gut flora in infancy predicted overweight later in childhood [28]. On average, overweight children had lower numbers of the genus Bifidobacterium spp. and higher numbers of Staphylococcus aureus in their stools during infancy.
Studies of lean and obese adult twin pairs found a core group of functional genes across participants regardless of bacterial species type. In addition to this “core microbiome”, the microbiomes of obese twins contained more genes involved in carbohydrate, lipid and amino acid metabolism [29].
These studies show the potential benefits of cross-disciplinary approaches for establishing key concepts of obesity intervention or prevention.
References
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A motivating discussion is worth comment. I do think that you need to publish more on this topic, it might not be a taboo subject but usually folks don’t speak about these topics. To the next! Kind regards!!