Apart from its important role in appetite regulation, leptin has a number of other central and peripheral actions – one of which is to increase activity of the sympathetic nervous system.
A paper by Wenwen Zeng and colleagues published in Cell, now provides conclusive evidence that leptin can mediate fat breakdown from fat cells and does so via stimulation of the sympathetic nervous system.
Using sophisticated nerve imaging techniques, the researchers show that fat cells are often densely surrounded by sympathetic nerve endings, which, when stimulated, lead to the mobilization of stored fat and a reduction in fat mass.
Genetic ablation of these nerve endings or removal of the key enzyme involved in catecholamine synthesis completely blocks the lipolytic effect of leptin showing that the fat mobilizing effect of leptin is entirely dependent on intact sympathetic innervation and signalling in fat tissue.
Overall the finding that sympathetic nerve activity stimulates lipid release in adipose tissue is not new – but the clear demonstration that his mechanism is harnessed by leptin is.
How this finding could possibly be harnessed for obesity treatment is difficult to say – while stimulating sympathetic nerve activity may well result in lipid mobilisation, it also comes with the feared adverse effects of stimulating heart rate and increasing blood pressure, which would likely limit the clinical use of any such approach.
Of all of the common complications of obesity, fatty liver disease is perhaps the most insidious. Often starting without clinical symptoms and little more than a mild increase in liver enzymes, it can progress to inflammation, fibrosis, cirrhosis and ultimate liver failure. It can also markedly increase the risk for hepatocellular cancer even in patients who do not progress to cirrhosis.
Now, a paper by Mary Rinella from Northwestern University, Chicago, published in JAMA provides a comprehensive overview of what we know and do not know about early detection and management of this┬ácondition.
The findings are based on a review of 16 randomized clinical trials, 44 cohort or case-control studies, 6 population-based studies, and 7 meta-analyses.
Overall between 75 million and 100 million individuals in the US┬áare estimated to have nonalcoholic fatty liver disease with 66% of individuals┬áolder than 50 years with diabetes or┬áobesity┬áhaving nonalcoholic steatohepatitis with advanced fibrosis.
Although the diagnosis and staging of fatty liver disease requires a liver biopsy, biomarkers (e.g. cytokeratin 18)┬ámay eventually┬áhelp in the detection of advanced fibrosis.
In addition, non-invasive imaging techniques including┬ávibration-controlled transient elastography, ultrasound with acoustic radiation force impulse or even magnetic resonance elastography are fairly accurate in the detection of hepatic fibrosis and are the most reliable modalities for the diagnosis of advanced fibrosis (cirrhosis or precirrhosis).
Currently, weight loss is the only proven treatment for fatty liver disease. Pharmacotherapy including treatment with┬ávitamin E, pioglitazone, and obeticholic acid may also provide some benefit (none of these treatments currently are approved for this indication by the UD FDA). Futhermore, the potential benefits of existing and emerging anti-obesity treatments on the incidence and progression of fatty liver remains to be established.
As Rinella points out,
“It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease.”
Clearly, screening for fatty liver disease needs to be part of every routine work up of individuals presenting with excess weight.
This year’s prestigious Fredrich┬áWassermann┬áAward of the European Association for the Study of Obesity presented at the 22nd European Congress on Obesity goes to Helsinki’s Aila Rissanen, Europe’s grande dame of obesity research.
I have personally known Aila for as lo as I have been involved in obesity and there is much in her work and approach to obesity that has stimulated my own thoughts on this issue.
In her acceptance address, Aila chose to focus on her work in BMI-discordant twins (among the many topics she has worked on) due to the remarkable insights into the “natre-nurture” discussion that this model offers.
Indeed, it is extremely rare to find genetically identical twins, who differ in body weight (demonstarting just how highly heritable body weight actually is). Thus, body weight in identical twins is remarkably homogeneous not only because of the heritability of weight per se but also due to heritability of weight gain.
Cining the work of her wildly successful trainee Kirsi Pietilainen, Aila described the efforts it took to identify just 30 obesity discordant (weight difference of >10 Kg) identical twins from well over 500 identical twin pairs.
These discordant twin pairs have now been extensively phenotyped with every imaginable laboratory test, measurement and tissue biopsies.
The most consistent difference between the discordant twins appears to be a greater level of physical activity in the leaner twin, which appears to precede the onset of weight gain.┬á In addition to voluntary physical exertion, there also appears to be a significant difference in fidgeting between the twins.
Compared to their co-twins, the obese twins had greater pro-inflammatory lipid profiles, lower antioxident activity and higher pro-coagulation markers. The reasons for these differences remains unclear.
Finally, Aila provided a brief overview of some of the exciting work that is now going on to further study the differences between these genetically identical but obesity disparate twins – metabolomics, lipidomics, epigenomics and even bacteriomics.
Although any of this has yet to translate to better obesity prevention or management, you never know where these fundamental insights into human biology may lead you.
For know, this is certainly a space I intend to watch.
Prague, Czech Republic
If you are┬áplanning to attend the 4th Canadian Obesity Summit in Toronto next week (and anyone else, who is interested), you can now download the program app on your mobile, tablet, laptop, desktop, eReader, or anywhere else -┬áthe app works on all major platforms and operating systems, even works offline.
You can access and download the app here.
(To watch a brief video on how to install this app on your device click here)
You can then create an individual profile (including photo) and a personalised day-by-day schedule.
Obviously, you can also search by speakers, topics, categories, and other criteria.
Hoping to see you at the Summit next week – have a great weekend!
With all of the recent interest in the gut microbiota as a mediator of systemic inflammation and metabolic disease, it was only a matter of time before researchers would begin targeting pro-inflammatory pathways in the gut to change metabolism.
A proof-of-principle, that this is indeed possible, is presented by Helen Luck and colleagues from the University of Toronto in a paper published in Cell Metabolism.
Using mice models, the researchers not only show that a high-fat diet can alter the┬águt immune system but also that the┬áchronic phenotypic pro-inflammatory shift in bowel lamina propria immune┬ácell┬ápopulations is reduced in genetically altered mice that lack beta7 integrin-deficient mice (Beta7null), a driver of gut inflammatory response.
Further more, treatment of high-fat-fed normal mice with the local gut anti-inflammatory agent 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters including insulin resistance (although it had no effect on body weight).
These beneficial effects are are associated with reduced gut permeability and endotoxemia as well as decreased visceral adipose tissue inflammation.
Moreover, treatment with ASA also improved antigen-specific tolerance to luminal antigens.
Thus, as the authors conclude,
“…the mucosal immune system affects multiple pathways associated with systemic insulin resistance┬áand represents a┬ánovel therapeutic target in this disease.”
Clearly gut inflammation both in relationship to gut microbiota as well as response to dietary factors is likely to be a hot topic in obesity and metabolic research for the foreseeable future.