Professor Dr Kerstin M Oltmanns of the University of Lübeck opens a new perspective on the epidemic of 2.2 billion overweight people
Obesity is a rising global health problem of an epidemic dimension. While underfeeding in the world declined slightly during the past two decades, the number of overweight people almost exploded in the same period.
According to the Institute for Health Metrics and Evaluation in Seattle (IHME), US, it is estimated that 2.2 billion individuals are overweight or suffer from its extreme form – obesity. This number derives from 2015. Since then the epidemic continues to spread. Generally, health problems of the overweight population comprise many secondary diseases such as diabetes mellitus, cardiovascular disease, certain forms of cancer, or mental illness. In turn, the numerous secondary diseases lead to considerable economic expenses and result in one of the most extensive cash disbursements in national healthcare budgets.
Despite intensive research and considerable amounts of public funding spent to unravel the underlying reasons of obesity, and preferably to identify an effective strategy to combat the problem, the underlying reasons why people overeat until they display a body mass index of at least 25 kg/m2 are still unknown.
Numerous studies at the organismic, cellular or molecular level did not lead to a breakthrough in this context. In fact, due to the unexplained reasons for excessive overeating, clinical obesity treatment stagnates for decades without any true innovation and is fraught with disappointment for attending physicians, as well as concerned individuals.
Biological view
At first sight, the biological explanation of how obesity develops is simple: a dysbalanced energy uptake and expenditure leads to ‘super-nutrition’ and makes the fat stores of an individual grow. In consequence, this should easily be reversed by caloric restriction in the form of diets and exercise.
However, disappointing outcomes of long-term clinical studies based on this strategy conclude that the problem is much more complex than this.1 Initially, diets represent an efficient treatment for weight loss, but in most cases bodyweight regain occurs after cessation of the caloric restriction, leading in the worst case to a higher record on the scales than before dieting – the so-called ‘yo-yo effect’.
Even more vexing is the proven fact that increased physical activity does not cause any significant weight loss unless combined with reduced calorie intake. This is because exercise drives appetite and, in contrast to the general assumption, burns up few calories. An alternative, which is becoming increasingly attractive, specifically to people with an extreme form of obesity, is bariatric surgery.
However, despite the unquestioned benefit of this treatment in some serious cases, bariatric surgery bears the risk of many severe complications, which precludes it to be considered an appropriate routine method in this context. The question remains why people overeat until they reach an unhealthy bodyweight – despite comprehensive basic knowledge about the disastrous consequences of their behaviour. In this context, current research finds that central nervous appetite regulation and specific neurocircuits are etiologically integrated in the pathomechanism.
These data seem to value obesity more as a neurobiological disease rather than a consequence of harmful food intake habits.
Neurobiological view
All biological functions of the organism are controlled and regulated by specific anatomic structures within the brain. In terms of food intake and appetite control, the lateral hypothalamus – a region in the interbrain – is responsible for hunger perception and initiates eating, whereas the ventromedial part of the hypothalamus gives the signal to stop food intake when satiety arises. But appetite control is not restricted to isolated hypothalamic regulation because all structures within the brain continuously interact with each other. Appetite regulation therefore underlies considerable influence, coming, for instance, from brain areas assigned to emotional processing and reward perception. The brain is therefore an extremely interesting and complex scientific field for obesity research.
In order to focus the brain as superordinate regulator of food intake control, and to address the role of central nervous appetite regulation and its disturbances, 15 years ago a group of scientists at the University of Lübeck, Germany, developed a model that explains the underlying pathogenesis of overweight and obesity.
Research on the so-called ‘Selfish Brain’ model has been funded as a clinical research group by the German Research Foundation (DFG, 2004-2010). The model postulates that the brain of overweight individuals is fundamentally undersupplied with energy (i.e. adenosine triphosphate (ATP), which is essential for a proper function of all cells within the organism).2
The consequence is that the brain’s ‘hunger centre’, localised within the lateral hypothalamus, perceives this undersupply, interprets this state as a life-threatening hunger crisis, and drives appetite and food intake irrespective of the growing body weight due to chronic overeating.3
Over the last ten years, our lab at the Section of Psychoneurobiology at the Centre of Brain, Behaviour and Metabolism of Lübeck University gave specific attention to this basic assumption of the model, i.e. the insufficient neuro-energetic state in obesity.
Indeed, confirming this hypothesis, our experimental research repeatedly showed that individuals with higher bodyweight display a decreased neuro-energetic level than those of ‘normal’ weight.4-6
Moreover, body mass index and brain energy content correlate negatively in a group of men with a body mass range between underweight, lean and obese.4 In this context, we found that obese individuals display a blunted brain energy consumption which relates to an atrophy in some specific brain structures responsible for central nervous processing of appetite and taste.6
Even more strikingly, we demonstrated that the brain energy content predicts the amount of subsequent food consumption, i.e. the lower the neuro-energetic state the more calories subjects consume and vice versa,7 which underpins the tight connection between brain energy homeostasis and food intake control.
Based on the insight that lowered brain energy status and overweight are interlinked, in the next step we concentrated on the question of whether the cerebral energy metabolism may be experimentally influenced and preferably elevated. Our simple hypothesis was that an elevated brain energy status would decline appetite and food consumption.
The first idea was to apply the anorexigenic hormone insulin via the intranasal route, i.e. as a spray. This application bears the advantage that the full dosage of insulin directly enters the brain, which would otherwise be hampered by a physiological barrier to protect the brain against harmful substances – the blood brain barrier – if applied orally or as an intravenous infusion.
Moreover, intranasal insulin application has been previously shown to decrease food intake in humans.
However, the underlying mechanism of this effect was completely unclear. We hypothesised that insulin facilitates neuronal glucose uptake via the insulin-dependent glucose transporter (GLUT4). Subsequently, glucose is intracellularly metabolised to gain energy, i.e. ATP, and thereby increases the energetic status.
In fact, nasal insulin spray induced an immediate rise at the neuro-energetic level and concomitantly suppressed food intake as expected.7 The brain energy content correlated negatively with subsequent calorie intake (i.e. the lower the neuro-energetic status the more people eat) and the neuro-energetic rise upon insulin administration correlated with the consecutive reduction in calorie consumption (i.e. the higher the energy rise after insulin application the lower subsequent food consumption).
Brain energy levels may therefore constitute a useful predictive value for food intake.
However, apart from intranasal insulin application, we discovered another effective method to increase the human brain’s energy status and thereby suppress food intake: transcranial direct current stimulation (tDCS) – i.e. electric stimulation of the brain.
For a couple of years, controlled transcranial electric stimulation of the brain has been part of treatment strategies in a number of neuropsychiatric diseases, but manipulating brain activity inevitably influences many bodily functions which underlie central nervous control.
We have been able to show that tDCS promotes systemic glucose uptake and improves human glucose metabolism,5 an effect which persists upon repeated daily application for eight days.8 This finding may open the vision of tDCS as a promising non-pharmacologic therapy option for diabetic patients in the future. But the beneficial effects of tDCS are not restricted to glucose homeostasis.
We also discovered that repetitive direct current stimulation of the brain, i.e. daily application for one week, unconsciously suppressed food consumption by a considerable 14%, mainly due to less carbohydrate intake.9
This work – funded by the German Research Foundation (DFG, TCRC 134) – attracted a lot of public attention because it gives hope to millions of obese people despairing of unsuccessful diet attempts.
So the surprisingly clear effect motivated us to further explore this innovative translational approach in a series of follow up studies, which are partially still ongoing. The first results are promising.
Psychoneurobiological view
Despite this pleasant perspective, the pure neurobiological point of view neglects one aspect, which is likewise well known as relevant but underestimated in obesity research to date: the psyche.1 Certainly everyone knows that psychological stress exerts a strong influence on food intake behaviour.
In this context, there is evidence that activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) – both constitute the body’s stress system – may contribute to the genesis of overweight.
Experimental data showed that the administration of glucocorticoids boosts food intake and stress-induced enhancement of blood cortisol concentrations relates to higher caloric intake as well as overeating and bodyweight gain in humans.
Both the activation of stress axes and the regulation of food intake behaviour are under central nervous control, interacting within the hypothalamus.
Acute stress enhances neuronal activity mainly within the hypothalamic and amygdala regions responsible for appetite regulation and emotional experience, which is associated with hyperphagia and obesity.
In terms of cerebral metabolism, it could be shown that neuronal activation upon psychological stress increases the cerebral metabolic rate for glucose by 12%, an effect that persists for more than 40 minutes after the intervention in healthy humans. In rats, immobilisation stress reduces cerebral energy, i.e. ATP levels, which – as we know from our studies – predicts increased food intake and relates to higher body weight.
But the influence of the psyche on food intake behaviour is not limited to stress, but is rather a common phenomenon in terms of many different states of mood.
The well-known neuro-energetic similarity between suppressed brain ATP levels both in obesity and clinically diagnosed depression is certainly not a pure coincidence. Generally, food intake in industrial societies is no more driven by feelings of physiological hunger and ends after one feels satiated. Quite the contrary, hunger and food consumption are increasingly disconnected in times of permanent access to foodstuffs for everyone.
In fact, food intake is mostly used by the individual to regulate emotional states. That is, people do not eat because they are hungry (this perception is mostly lost in obesity, as well as feelings of satiety) but because of stress, frustration, sadness, or even simply boredom, etc. Eating appeases and reduces bad feelings as scientific studies have repeatedly shown. This behaviour is called ‘emotional eating’, and dieting for weight loss even worsens the problem of dysfunctional hunger and satiety perception because it strictly prescribes what and how much one must eat. Under these circumstances of external pre-setting, it is not possible to develop a physiological appetite regulation again.
No surprise that after the diet people quickly regain weight. Meanwhile, a considerable number of studies confirmed that dieting, sports and pharmacological methods for weight loss are simply inefficient in the long run.1
So, after 20 years of intense international obesity research and billions of euros spent for research funding, standard therapies for weight loss still comprise diets and sport programmes.
With regard to the current estimate of 2.2 billion overweight people worldwide, this persistence in little effective clinical recommendations amounts to a capitulation. New strategies are therefore urgently required.
The novel approach to obesity – hands-off dieting
To meet this problem, the idea emerged to develop a novel approach which aims to change food intake behaviour per se, instead of prescribing foodstuff choice as diets do. Obese people should learn to distinguish between psychological needs and physiological hunger to avoid ‘emotional’ food consumption, and thereby overeating.
Proven behavioural therapeutic methods applied by an interactive computer program should help to perceive feelings of satiety/hunger again and normalise eating habits – and therefore bodyweight in the long run.
Importantly, the concept forgoes any diets, foodstuff instructions and calorie counting, which hampers physiological nutrition driven by natural hypothalamic regulation. Because studies have shown that food consumption is tightly related to the activation of neuro-anatomic structures assigned to reward perception, the novel concept stimulates this part of the brain in the form of a game which also serves to distract the individual in situations of an imminent binge eating attack.
Moreover, stress coping strategies are an essential part of the programme as stress is known as the most important reason to initiate ‘emotional eating’.
Meanwhile, the award-winning concept has been developed and is available as a commercial product in the form of a mobile app in German and English (www.nupp.de). Currently, we examine the efficiency of the underlying strategy to lose bodyweight and normalise food intake habits in a scientific study.
First data are promising and reveal significant weight loss after one month of using the system. It is therefore planned to explore the effects of the programme on a number of psychological, neurobiological, and neuro-energetic aspects known to be disturbed in obesity. In any case, the currently most valuable slogan for successful strategies to combat the obesity epidemic seems to be ‘stop dieting, learn to perceive hunger and appetite again, and don’t eat for emotional reasons’. We must impede the epidemic.
References
- Jauch-Chara K and Oltmanns KM: Obesity – a neuropsychological disease? Systematic review and neuropsychological model. Prog Neurobiol 114:84-101, 2014
2. Peters A, Schweiger U, Pellerin L, Hubold C, Oltmanns KM, Conrad M, Schultes B, Born J, Fehm HL: The selfish brain: competition for energy resources. Neurosci Biobehav Rev 28:143-180, 2004
3. Peters A, Pellerin L, Dallman MF, Oltmanns KM, Schweiger U, Born J, Fehm HL: Causes of obesity: Looking beyond the hypothalamus. Prog Neurobiol 81:61-88, 2007
4. Schmoller A, Hass T, Strugovshchikova O, Melchert UH, Scholand-Engler HG, Peters A, Schweiger U, Hohagen F, Oltmanns KM: Evidence for a relationship between body mass and energy metabolism in the human brain. J Cereb Blood Flow Metab 30:1403-1410, 2010 (Ernst und Berta Scharrer Award, German Society of Endocrinology 2009)
5. Binkofski F, Loebig M, Jauch-Chara K, Bergmann S, Melchert UH, Scholand-Engler HG, Schweiger U, Pellerin L, Oltmanns KM: Brain energy consumption induced by electrical stimulation promotes systemic glucose uptake. Biol Psychiatry 70:690-695, 2011
6. Jauch-Chara K, Binkofski F, Loebig M, Reetz K, Jahn G, Melchert UH, Schweiger U and Oltmanns KM: Blunted brain energy consumption relates to insula atrophy and impaired glucose tolerance in obesity. Diabetes 64:2082-91, 2015
7. Jauch-Chara K, Friedrich A, Rezmer M, Melchert UH, Scholand-Engler HG, Hallschmid M, Oltmanns KM: Intranasal Insulin Suppresses Food Intake via Enhancement of Brain Energy Levels in Humans. Diabetes 61:2261-2268, 2012
8. Kistenmacher A, Manneck S, Wardzinski EK, Martens JC, Gohla G, Melchert UH, Jauch-Chara K and Oltmanns KM: Persistent blood glucose reduction upon repeated transcranial electric stimulation in men. Brain Stimul 10:780-86, 2017
9. Jauch-Chara K, Kistenmacher A, Herzog N, Schwarz M, Schweiger U and Oltmanns KM: Repetitive electric brain stimulation reduces food intake in humans. Am J Clin Nutr 100:1003-9, 2014
