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.
However, there is also new data suggesting that altered immune function may well be an important causal step in the accumulation of excess fat and related metabolic abnormalities.
Two studies, both in animal models, point to a role of perforin, a cytotoxic effector molecule primarily released by CD8+ T cells and natural killer (NK) cells to eliminate infected or dangerous cells via the perforin-granzyme cell death pathway. In rare cases of humans with impaired perforin-dependent cytotoxic function, one often sees excessive T-cell activation, severe hyper-inflammation and possibly death.
The first study by Xavier Revelo and colleagues from the University of Toronto, published in Diabetes, perforin-deficient mice (Prf1null), which show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD) were shown to have an increased accumulation of proinflammatory IFN-γ–producing CD4+ and CD8+ T cells and M1-polarized macrophages in visceral adipose tissue.
Furthermore, transfer of CD8+ T cells from Prf1null mice into CD8-deficient mice (CD8null) resulted in worsening of metabolic parameters compared with wild-type donors, thus demonstrating a role for T-cell function in insulin resistance associated with visceral adipose tissue.
In a second independent study by Yael Zlotnikov-Klionsky and colleagues from the Weizmann Institute of Science in Rehovot, Israel, published in Immunity, showed that animals selectively lacking perforin-rich granules in their dendritic cells, progressively gained weight and exhibited features of metabolic syndrome, an effect that could be completely prevented by T cell depletion.
Both studies show that the immunoregulatory protein perforin appears to be an important regulator or body weight and metabolic function – a finding, which may well open a new door biological drivers of obesity.
Incidentally, perforin also plays a role in auto-immune diseases and this finding may thus provide a link between the common occurrence of obesity in people with auto-immune disease and has led some authors to even suggest that obesity itself may be a form of auto-immune disease.
While the therapeutic options will certainly not be as simple as replacing low levels of perforin, understanding exactly how immune function ties into the regulation of body weight may eventually lead to novel targets.
Dietitians play an often critical role in helping patients with obesity better manage their weight.
However, I also know that dietitians are the first to agree that obesity management is not just about diet (and exercise) but rather, that diet is just one aspect of an interdisciplinary management approach.
The two-day retreat (October 7-8, Toronto), which follows a highly intense interactive workshop format, covers all aspects of interdisciplinary obesity management including behavioural, medical and surgical treatments. There will also be a special focus on the nutritional management of bariatric patients as well as weight-sensitive behavioural modification.
Speakers at the event include Michael Vallis, Eric Doucet, Jennifer Brown-Vowles, Sean Wharton, and myself.
The course is open to all registered dietitians and anyone else interested in (not-just) nutritional aspects of obesity management.
For advanced registration (early bird registration ends Sept 15) and more information click here.
In my conversations with skinny runners, they often cannot stop telling me how much satisfaction and enjoyment they get from their “runner’s high”. No wonder, they so often seem “addicted” to their runs (or other workouts).
In contrast, a “runner’s high” seldom comes up when any of my patients living with obesity talk about their exercise experiences (yes, many people with obesity exercise regularly).
Now, work by Maria Fernandes and colleagues from the University of Montreal, published in Cell Metabolism, reports findings in rats, which, if applicable to humans, may provide a biological explanation for this observation.
Building on previous studies showing that leptin modulates multiple components of brain reward circuitry, particularly in dopamine (DA) neurons of the ventral tegmental area (VTA), an area of the brain allegedly responsible for the “runner’s high”.
Using an elegant set of experiments, the researchers showed that leptin markedly reduces mice’s willingness to work for access to a running wheel or show other signs of seeking out exercise-induced reward.
In contrast, mice with a deletion of the signal transducer and activator of transcription-3 (STAT3), involved in leptin signalling in dopamine neurons of the VTA, showed greater interest in voluntary running.
In other words, STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner.
Together these findings strongly suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone.
Or, in other words, higher levels of leptin (as seen in people living with obesity) directly inhibit the rewarding nature of running, making it less likely to experience a runner’s high, than in someone with low leptin levels (as seen in people with low fat mass).
As to why this may be the case, the authors offer the following explanation:
“We speculate that in conditions of restricted food availability the mesolimbic DA system engages motivational processes concerned with obtaining food and more readily responds to leptin to decrease appetitive physical activity. On the other hand, during fed states, the actions of leptin may be biased toward hypothalamic processes that could increase physical activity as a means to maintain energy homeostasis.”
“While heightened physical activity during food restriction seems paradoxical to the maintenance of energy reserves, it is considered an expression of increased food acquisition behaviors. The capacity for endurance running in cursorial mammals is considered to enable food attainment when it is distant or requires pursuit. Correspondingly, the runner’s high may have evolved to encourage stamina and thereby increase the probability of return on this energetic investment.”
As the authors note, this line of reasoning is supported by the recent observation that exercise addiction in men is associated with low, fat-adjusted leptin levels.
In light of these findings, I also wonder if the “increase in energy levels”, which is rather consistently reported by my patients when they lose weight, may simply be reflective of their often dramatic reduction in leptin levels.
Anyone even remotely familiar with cannabis use and its potential to cause the “munchies” would immediately assume that regular cannabis use would likely promote weight gain and, in consequence, the risk forf type 2 diabetes.
Thus, readers may well be as intrigued as I am by the work of Gerard Ngueta and colleagues from Québec, Canada, published in OBESITY, showing a rather strong inverse association between cannabis use and BMI in the Inuit.
The researchers analyzed data from 786 Inuit adults from the Nunavik Inuit Health Survey (2004), which included self-reported use of cannabis as well as measured levels of fasting blood glucose and insulin.
Not only was cannabis use highly prevalent in the study population (57%), but even after adjustment for a number of potential confounders, cannabis use was significantly associated with lower body mass index (BMI) (about 2 BMI points, P < 0.001), lower % fat mass (P < 0.001), lower fasting insulin (P = 0.04), and lower HOMA-IR (P = 0.01).
In multivariate analysis, past-year cannabis use was associated with 0.56 lower likelihood of obesity (95% confidence interval 0.37-0.84), and it was this relationship that fully explained the seemingly positive effect of cannabis use on insulin resistance (as a surrogate for diabetes risk).
It may also be worth noting that the association of cannabis use with lower BMI was only seen in past or non-smokers, but not in current tobacco smokers.
Now normally, being highly sceptical of these types of association studies, which are generally hopelessly confounded and can never prove causality, I would have dismissed this as a chance finding of little significance.
Imagine my surprise, however, when the authors go on to mention several previous studies, in a variety of populations, that have reported similar findings.
Unfortunately, the authors have little to offer in terms of a plausible biological mechanism and can only speculate on possible genetic or functional factors involving the cannabinoid system or putative effects on energy expenditure associated with the pulmonary consequences of smoking.
Thus, I can presently make little of this finding – but I will likely stay tuned.