While I took a month off from blogging, an international group of researchers published what may well become a landmark paper on the genetics of obesity in the New England Journal of Medicine.
As regular readers may be well aware, a number of previous genetic studies have pointed to the importance of the FTO gene for human obesity – however, what exactly this gene does to effect body weight was largely unclear.
The rs1421085 single-nucleotide variant of this gene has both a high frequency and a strong effect size, which suggests positive selection or bottlenecks (e.g., 44% frequency in European populations vs. 5% in African populations).
In the present paper, that included examination of epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns in mice and humans, the researchers showed that the FTO allele associated with obesity represses mitochondrial energy production in adipocyte precursor cells in a tissue-autonomous manner.
To be precise, the rs1421085 variant of this gene apparently disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. These molecules play key roles in thermogenic dissipation both through UCP-1 and UCP-1-independent pathways.
This change leads to a persistent and cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5. It is also associated with an increase in lipid storage and adipocyte cell size.
Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite.
Knockdown of IRX3 or IRX5 in primary adipocytes from human subjects with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers.
Finally, repair of the ARID5B motif in primary cultured adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7.
These deep insights into the function of what is apparently a key pathway in human susceptibility (or resistance) to obesity, offers a number of potential targets for pharmacological interventions for obesity – something that we desperately need for patients struggling with this issue.
However, as an accompanying editorial is quick to point out,
“As yet, there is still no simple path to an anti-obesity drug that can be derived from this research.”
Then again, who expects finding new treatments for obesity to be simple?
To conclude this brief series on our new exhaustive review of the putative health benefits of long-term weight-loss maintenance, published in Annual Reviews of Nutrition, here is the summary paragraph of our findings:
“Obesity is well recognized as a risk factor for a wide range of health issues affecting virtually every organ system. There is now considerable evidence that intentional weight loss is associated with clinically relevant benefits for the majority of these health issues. However, the degree of weight loss that must be achieved and sustained to reap these benefits varies widely between comorbidities. Downsides of weight loss that is too rapid and/or extreme may occur, as in the increased risk of gallbladder disease, the presence of excess residual skin, or deterioration in liver histology. Uncertainty also remains about the potential benefit or harm of intentional weight loss on patients presenting with some chronic diseases and on overall mortality. Clearly, well- controlled prospective studies are needed to better understand the natural history of obesity and the impact of weight-management interventions on morbidity, quality of life, and mortality in people living with obesity.”
The is much left to be done and answering some of these questions will become progressively easier as better treatments for obesity become available.
While the health benefits associated with intentional weight loss for some complications of obesity (such as elevated lipids and diabetes) are well documented, high-quality studies to back many other potential health benefits are harder to find.
Just how well (or poorly) the putative health benefits of long-term intentional weight loss are documented for each of the many conditions associated with obesity, is now detailed in a comprehensive review of the literature that we just published in the Annual Reviews of Nutrition.
The 40 page long review, which includes almost 250 relevant publications, supports the following main findings:
- Defining and assessing clinically relevant obesity and weight change are challenging tasks. In a given individual, there is often little relationship between the magnitude of obesity and measures of health.
- Despite its modest effect on long-term weight loss, behavioral modifications thatimprove eating behaviors and increase physical activity constitute a cornerstone for integral and sustainable weight management.
- Intentional weight loss is associated with a clinically relevant reduction in blood pressure, improvement in cardiac function, and reduction in cardiovascular events. The duration and magnitude of weight change required to achieve a significant benefit are still unclear.
- In individuals with impaired glucose metabolism at any stage, intentional weight loss achieved by any means is associated with a proportional reduction in T2DM prevalence, severity, and progression.
- Intentional weight loss is consistently associated with a clinically relevant reduction in triglycerides and increase in HDL cholesterol. The effects of weight loss on LDL cholesterol are less consistent.
- Overall, nonalcoholic fatty liver disease is commonly associated with excess weight and can show marked improvement with behavioral, pharmacological, and/or surgical weight loss. Very rapid weight loss, however, may worsen liver histology in some patients. Simi- larly, gallbladder disease is not only common in patients presenting with obesity but also highly prevalent after intentional weight loss.
- Obesity is widely recognized as a key modifiable risk factor for osteoarthritis, with sig- nificant improvements in pain and function reported with weight loss.
- Obstructive sleep apnea and obesity hypoventilation syndrome tend to improve with moderate weight loss; however, complete resolution is not common and is related to very significant weight loss.
- Asthma and COPD are clearly associated with obesity. Sustained weight loss seems to be associated with a significant improvement in asthma symptoms. Data for COPD are rather limited.
- Pregnant women who under go bariatric surgery seem to be less likely to present obstetric complications such as gestational diabetes, preeclampsia, and macrosomia.
- Data on weight loss and suicide are controversial. Caution may be in order when con- sidering bariatric surgery in patients with a history of suicide ideation or attempt.
- Data suggest that long-term weight loss is associated with an improvement in health- related quality of life. The amount of weight loss required to achieve a significant change, however, remains controversial.
However, there are many other issues where putative benefits of intentional weight loss remain even less clear than with the above.
For many conditions we will likely not know the long-term benefits of obesity treatments till better treatments become available and are tested in affected individuals.
While I’m here at the 10th Canadian Obesity Network Summer School (Boot Camp), in the Canadian Rockies, it is perhaps of interest to note that one of the founding faculty of this school, Denis Richard from Laval University, has just published a paper in Nature Reviews Endocrinology, which nicely reviews the complex neurobiology of energy balance.
The paper focuses largely on the “energy out” part of energy homeostasis, which is partly determined by the themogenesis of brown adipose tissue and mediated by the sympathetic nervous system.
Thus, several areas of the brain work together in complex neuronal networks involving a host of neuronal systems including the opioid, endocannabinoid and melanocortin systems, that not only control appetite and eating behaviour but also thermogenesis.
These neuronal systems, in turn receive inputs from a wide range of peripheral organs including the gut, liver and adipose tissue via hormonal and neuronal pathways that signal energy stores and nutritional status.
The paper also discusses how some of these findings may be relevant to the development of novel treatments for obesity.
For researchers and students: the paper includes a number of excellent graphics that nicely illustrate these systems.
The amygdala is a part of the so-called limbic system that performs a primary role in the processing of memory, decision-making, and emotional reactions. The amygdala has also been implicated in a variety of mental health problems including anxiety, binge drinking and post-traumatic stress syndrome.
A study by Xu and colleagues, published in the Journal of Clinical Investigation now shows that in mice, activity of the estrogen receptor–α (ERα) in the medial amygdala may have a profound influence on the development of obesity – an effect, which appears to me largely mediated through effects on physical activity.
Building on previous work showing that ERα activity in the brain prevents obesity in both males and female rats, the researchers used a series of complex experiments to demonstrate that specific deletion of the ERα gene from SIM1 neurons, which are highly expressed in the medial amygdala, cause a marked decrease in physical activity and weight gain in both male and female mice fed with regular chow, without any increase in food intake. In addition, this deletion caused increased susceptibility to diet-induced obesity in males but not in females.
Deletion of the ERα receptor also blunted the body weight-lowering effects of a glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate.
In contrast, over-expression or stimulation of SIM1 neurons increased physical activity in mice and protected them from diet-induced obesity.
These findings point to a novel mechanism of neuronal control of physical activity, which in turn appears to have important effects on the susceptibility to weight gain.