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.
It turns out that this is not exactly what happens in actual clinical practice – indeed, patients with excess weight almost never go to see their doctor specifically for this reason.
Rather, patients primarily go to their doctors for help with any of the many health conditions associated with obesity – problems ranging from high blood pressure and diabetes to sleep apnea, arthritis or infertility.
In other words, obesity rarely presents as a discreet health problem – rather, it is “embedded” in other health issues.
This is the (perhaps, when you think about it, not quite so surprising, ) finding of a study by Asselin and colleagues from the University of Alberta, published in Clinical Obesity.
The 5As Team study was designed to create, implement and evaluate a flexible intervention to improve the quality and quantity of weight management visits in primary care.
To gain a better understanding of current practice, we conducted semi-structured interviews with 29 multidisciplinary team providers and field notes of intervention sessions.
A key pattern that emerged from the thematic analysis of the data was that patients do not present, nor do healthcare providers usually address obesity as a primary focus for a visit. Rather, obesity is generally “embedded” in a wide range of primary care encounters for other conditions.
This finding has important implications for clinical practice.
For one, when patients present to their health care provider with a specific problem, be it diabetes, sleep apnea, or knee pain, they want their provider to discuss their diabetes, sleep apnea or knee pain – they are not interested in hearing about their weight issues.
On the other hand, when providers see patients presenting with diabetes, sleep apnea or knee pain, it already uses up all their limited time to talk about diabetes, sleep apnea or knee pain, so tagging on a meaningful discussion of weight is simply not feasible.
These observations suggest that obesity treatment approaches and tools that assume a discreet weight management visit are doomed to fail, as they do not represent or fit into the current way of practice.
On a positive note, the embedded nature of obesity management can potentially be harnessed to leverage multiple opportunities for asking and assessing root causes of obesity, and working longitudinally towards individual health goals (as laid out in the 5As framework).
Thus, for providers it may be as simple as tactfully and non-judgementally (after first discussing the primary problem) asking if the patient has concerns or would also like to also discuss their weight issues – if yes, this should prompt the booking of a separate and discreet appointment with a focus on discussing this problem, rather than simply throwing out some advice (“eat-less-move-more”).
For people struggling with their weight reading this, the lesson is that if you want your health professional’s help in addressing your weight, then book a specific appointment for exactly that, rather than trying to have a meaningful discussion about this when you happen to be there for something else.
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.
While this is increasingly being appreciated in adults, data on childhood cancer survivors is rather sparse.
Thus, a study by Carmen Wilson and colleagues, published in Cancer, which follows the development of obesity in individuals treated for cancer as kids is of particular interest.
The study looks at 1996 cancer survivors who previously received treatment for cancer at a large Children’s Research Hospital, who survived ≥10 years from diagnosis (median age at diagnosis, 7.2 years; median age at follow-up, 32.4 years).
Interestingly, 47% of survivors, who received cranial radiation therapy developed obesity compared to only 30% of those who did not.
This risk was greatest in those who also received glucocorticoids or were the youngest at the time of treatment.
The researchers also found a significant modifying effect of genetic markers, some of which are known to be involved in neural growth, repair and connectivity.
Thus, this study shows that survivors of childhood cancer appear to be prone to developing obesity as adults particularly if they were treated with cranial radiation therapy and/or corticosteroids.
Clinicians should be aware of this increased risk and should consider measures to prevent excess weight gain in individuals with a history of childhood cancer.
Wilson CL, Liu W, Yang JJ, Kang G, Ojha RP, Neale GA, Srivastava DK, Gurney JG, Hudson MM, Robison LL, & Ness KK (2015). Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. Cancer PMID: 25963547
And finally, to conclude this week’s discussion of evidence to support the notion that weight cycling predicts weight (fat) gain especially in normal weight individuals, I turn back to the paper by Dulloo and colleagues published in Obesity Reviews, which quotes these interesting findings in US Rangers:
“…U.S. Army Ranger School where about 12% of weight loss was observed following 8–9 weeks of training in a multi-stressor environment that includes energy deficit. Nindl et al. reported that at week 5 in the post-training recovery phase, body weight had overshot by 5 kg, reflected primarily in large gains in fat mass, and that all the 10 subjects in that study had higher fat mass than before weight lost. Similarly, in another 8 weeks of U.S. Army Ranger training course that consisted of four repeated cycles of restricted energy intake and refeeding, Friedl et al. showed that more weight was regained than was lost after 5 weeks of recovery following training cessation, with substantial fat overshooting (∼4 kg on average) representing an absolute increase of 40% in body fat compared with pre-training levels. From the data obtained in a parallel group of subjects, they showed that hyperphagia peaked at ∼4 weeks post-training, thereby suggesting that hyperphagia was likely persisting over the last week of refeeding, during which body fat had already exceeded baseline levels.”
Obviously, association (even in a prospective cohort) does not prove causality or, for that matter, provide insights into the physiological mechanisms underlying this observation.
All we can conclude, is that these observations in US Rangers (and the other studies cited in Dulloo’s article) are consistent with the notion that weight loss in normal weight individuals can be followed by significant weight gain, often overshooting initial weight.
Incidentally, these findings are also consistent with observational studies in women recovering from anorexia nervosa, famine, cancer survivors and other situations resulting in significant weight loss in normal weight individuals.
Certainly enough evidence to consider a work of caution against “recreational” weight loss, especially in individuals of normal weight.
Dulloo AG, Jacquet J, Montani JP, & Schutz Y (2015). How dieting makes the lean fatter: from a perspective of body composition autoregulation through adipostats and proteinstats awaiting discovery. Obesity reviews : an official journal of the International Association for the Study of Obesity, 16 Suppl 1, 25-35 PMID: 25614201