Thus, a study by Claire Chevalier and colleagues from Geneva, Switzerland, published in CELL, not only shows that cold exposure (of mice) changes their gut microbes but also that, when transplanted into sterile mice, these “cold” microbes stimulate the formation of thermogenic brown fat.
All of this makes evolutionary sense, as the increase in heat-generating (and calorie-burning) brown fat with cold exposure would protect the organism against cold exposure – however, that gut bacteria would be involved in this process is indeed rather surprising.
Unfortunately, at least for those thinking that “cold bacteria” may be the panacea for stimulating brown fat and thus weight loss are likely to be disappointed.
The researchers also show that with prolonged exposure to cold, these “cold bacteria” induce changes to the structure and function of the gut that enable more glucose to be absorbed.
While in the short-term, this extra fuel can be used by the brown fat to generate heat, in the long-term, some of these extra calories probably go towards building more white fat and thus weight gain.
Again, this makes evolutionary sense. After all, it is ecologically a far better strategy to insulate the house than to waste extra calories heating it.
This is why, the naive notion that simply lowering ambient temperature as a means to generate more brown fat and thus, burn more calories, may not be all that effective.
Indeed, these experiments suggest rather that chronic cold exposure would ultimately stimulate extra insulation, i.e. more subcutaneous fat and weight gain.
Funnily enough, these findings turn the hypothesis that reducing room temperature would promote weight loss into exactly the opposite. Perhaps it is the excessive use of air-conditioning to generate freezing indoor temperatures (as any European visitor to the US will readily attest to), is part of the problem.
Fascinating stuff for sure.
To students of human physiology, the commonly held view that obesity is simply a matter of energy in and energy out is nothing short of laughable.
Indeed, there are perhaps no other biological functions of more importance for survival of an organism, than those that regulate energy uptake, storage and expenditure – functions, without any form of life would be impossible.
Thus, the finely tuned complex and often highly redundant pathways that have evolved to optimize energy metabolism have evolved to readily switch from states of feeding to starvation with shifts in substrate use (both qualitative and quantitative) – functions that are controlled by hundreds (if not thousands) of genes.
Getting these genes to work in concert, requires a complex system of gene regulation, by which individual genes are switched on an off (to allow or stop protein synthesis) in various tissues to just the right amount at just the right time – a process known as transcriptional control.
Now, a comprehensive review by Adelheid Lempradl and colleagues, published in Nature Genetics, summarizes the multitude of interlinked processes that control transcription of genes involved in energy homeostasis.
As the authors explain,
“Transcriptional control is the sum of the cellular events that select and dose gene transcription. In simple terms, these events converge on the regulation of gene locus accessibility and polymerase activity (including recruitment, pausing, processivity and termination).”
“Energy homeostasis requires multi-layered regulation via dynamic, often periodic, expression of metabolic pathways to properly anticipate and respond to shifts in energy state.”
“Transcription factors act by binding to specific regulatory DNA sequences, thus controlling the transcriptional output of defined target gene sets. They cooperate with co-regulators, which either promote (co-activators) or inhibit (co-repressors) transcription. Together, they build feedback networks and control the stability and responsiveness of energy homeostasis. Metabolic cells use receptors and metabolic machinery to generate specific signalling responses to endocrine inputs (for example, insulin, glucagon or leptin receptors) or metabolic inputs (for example, the primary energy metabolism machinery itself).”
The papers goes on to discuss at length the various regulator, co-regulators and the plethora of epigenetic modifiers that determine how these factors do their job of activating or deactivating relevant genes throughout the body.
Why is any of this important?
“Rapid progress is currently being made in research on chromatin-based regulation of gene expression. Particular unknowns include the mechanisms that establish long-term set points or priming of gene expression. Identifying the processes that establish activation thresholds and maximal output set points, as well as their self-organizing principles is currently an intriguing area of research, and is important in understanding susceptibility to complex trait disorders, including metabolic and autoimmune diseases. For example, many intergenerational and developmental reprogramming paradigms elicit metabolic disease susceptibility. They highlight the potential impact of subtly divergent transcriptional profiles in any given genetic context.”
In other words, understanding these processes are fundamental for our understanding of everything from the body’s weight set point (and how this is altered) to intergenerational transmission of obesity risk from one generation to the next (perhaps the most important driver of the current obesity epidemic).
But the complexity of these processes also raise important issues for clinicians,
“The seemingly exponential growth in this complexity now poses a major challenge for translational researchers in need of simplified but accurate paradigms for clinical use.”
The least we can do is to stop pretending that there is anything easy about energy in and energy out.
As Canada’s national representative in the World Obesity Federation (formerly IASO), the Canadian Obesity Network is proud to co-host the 13th International Congress on Obesity in Vancouver, 1-4 May 2016.
The comprehensive scientific program will span 6 topic areas:
Track 1: From genes to cells
- For example: genetics, metagenomics, epigenetics, regulation of mRNA and non–coding RNA, inflammation, lipids, mitochondria and cellular organelles, stem cells, signal transduction, white, brite and brown adipocytes
Track 2: From cells to integrative biology
- For example: neurobiology, appetite and feeding, energy balance, thermogenesis, inflammation and immunity, adipokines, hormones, circadian rhythms, crosstalk, nutrient sensing, signal transduction, tissue plasticity, fetal programming, metabolism, gut microbiome
Track 3: Determinants, assessments and consequences
- For example: assessment and measurement issues, nutrition, physical activity, modifiable risk behaviours, sleep, DoHAD, gut microbiome, Healthy obese, gender differences, biomarkers, body composition, fat distribution, diabetes, cancer, NAFLD, OSA, cardiovascular disease, osteoarthritis, mental health, stigma
Track 4: Clinical management
- For example: diet, exercise, behaviour therapies, psychology, sleep, VLEDs, pharmacotherapy, multidisciplinary therapy, bariatric surgery, new devices, e-technology, biomarkers, cost effectiveness, health services delivery, equity, personalised medicine
Track 5: Populations and population health
- For example: equity, pre natal and early nutrition, epidemiology, inequalities, marketing, workplace, school, role of industry, social determinants, population assessments, regional and ethnic differences, built environment, food environment, economics
Track 6: Actions, interventions and policies
- For example: health promotion, primary prevention, interventions in different settings, health systems and services, e-technology, marketing, economics (pricing, taxation, distribution, subsidy), environmental issues, government actions, stakeholder and industry issues, ethical issues
Early-bird registration is now open – click here
Abstract submission deadline is November 30, 2015 – click here
For more information including sponsorship and exhibiting at ICO 2016 – click here
I look forward to welcoming you to Vancouver next year.
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.