How are fat cells related to depression?

Much literature discusses chronic inflammatory diseases as the most significant cause of mortality and morbidity in the world. Obesity and depression are chronic inflammatory diseases and the so-called ‘obesity and depression epidemic’, highlights this growing disease burden. Now estimated worldwide at over 300 million people suffering from depression [1], and 650 million obese [2]. 

Obesity is measured via an established diagnostic called Body Mass Index, estimated by dividing weight in kg by height in m2 (or BMI >= 30 kg/m2) [3]. Depression is measured via various depression assessment instruments. Examples of such instruments and scales can be found in the U.S. psychiatry manual DSM-5 and the European psychiatry manual ICD-11 .

The high disease burden of obesity associated with depression in chronic patients confers high heterogeneity. This means their respective underlying aetiologies (manner of causation) are mediated by a complex interaction of genetic, neurobiological, behavioural, and social factors. This can include psychosocial stress-induced anxiety, isolation or even loneliness and economic hardship. The statistics obscure the suffering, when considering this high heterogeneity alongside varying severity levels in obesity and depression disease, and overall reduced quality of life. Hence the importance of this discussion. 

One determinant of obesity and depression comorbidity (or simultaneous presence), is dysfunctional fat mass. BMI increasing above the normal range (18.5 – 24.9 kg/m2) for prolonged periods over months or years, has been associated with persistent immune activation and low-level systemic inflammation. Exacerbating risk for obesity-related depression and vice versa. Also, increasing risk for secondary conditions, including heart disease, type II diabetes [4] and more recently covid, where inflammation has been shown to underlie severe covid symptomology. 

Inflammation is the body’s natural immune defence mechanism in good health, with first line defence (when pathogens attack), being the body’s own cell-mediated immune response, involving cytokines vs. antibodies. However, this defence can become impaired in obesity, when fat cell’s usual synthesis of anti-pro- inflammatory adipocytokines becomes skewed toward pro-inflammatory. Elevated levels of pro-inflammatory adipocytokines Interleukin 6 (IL-6), C-reactive Protein (CRP), Tumour Necrosis Factor-alpha (TNF-α), and Leptin, also Resistin (in conjunction with higher fasting serum insulin), have been found in obese adipose (fat) tissue [6]. Coining a  neuro-inflammation subtype where the fat cells in this subtype ‘act as if’ they are defending against pathogens, when they are actually defending against their own inflamed state [7]. 

Speculating the cytokine hypothesis, whereby much empirical evidence has been gathered over the past two decades, linking obesity risk with inflammation in depression. Patients characteristically exhibit abnormal levels of pro-inflammatory adipocytokines IL-6, CRP, and TNF-α blood biomarkers, and have impaired immune responses, in comparison with non-obese-depressed patients. Interestingly, in studies administering HIV-inductive cytokines, including TNF-α and IL-6, found depressive symptomology and behaviours could be induced in some patients, such as anxiety, anhedonia, and disordered feeding behaviours [8]. 

There is a relationship between fat cell size and volume in obesity and elevated pro-inflammatory adipocytokines, shown to aggravate the neuroinflammation subtype. Potentially leading to deposition of fat in other organs, mainly the liver, with consequences of fatty liver disease, as well as poor gut microbe health. In addition, elevated levels of TNF-α and resistin have been shown to induce insulin resistance, driving obesity traits, where your risk of developing depression is double that of someone who is not insulin-resistant, even if you have never experienced depression before. Insulin resistance is also associated with type 2 diabetes and impaired stress response. People with diabetes are two to three times more likely to have depression than people without diabetes [9][10]. 

Elevated IL-6 has been shown to play a significant role in the accumulation of fat cells in the muscular tissue of the heart, driving factors that can lead to heart disease. While higher levels of leptin have been shown to increase leptin resistance in the brain, which means the brain does not respond as it normally would to leptin. Leptin resistance ‘turns off’ leptin’s inter-cellular signals that would normally tell the body to stop eating, so you do not feel satiated, underlying disordered eating, even if you have sufficient fat stores [11].

Interestingly, the Covid-19 pandemic has illuminated high-BMI related chronic inflammation and impaired immunity as strong independent risk factors for severe Covid disease, heightening the risk of the illness in patients with obesity. Particularly in a subgroup, comorbid with metabolic syndrome, shown to be more prone to developing ‘hyper inflammation and cytokine storm syndrome’ [12]. Emphasised in a study by Tulane University that found ‘metabolic syndrome itself substantially increased the risks of ICU admission, ventilation and mortality’ [13]. Further qualified by a recent peer-reviewed study, showing similar findings [14]. 

Alongside, an on-going Covid-19 Social Study by University College London (UCL), found ‘levels of depression and anxiety remained highest among those with a pre-existing clinical diagnosis of depression and obesity, living with lower household income…, in urban areas’, relating environment and health inequalities as fundamental in the covid phenomena[15]. Other twin studies (Afari et al., 2010) also highlighted the role of the environment and related psychosocial stressors in the pathologic mix, in finding that ‘only 12% of the genetic component of depression is shared by obesity’ [17]. 

Moreover, a study by Kings College London, looking at genetic predisposition in body weight regulation, showed a link between clinical eating disorders (binge-eating and bulimia) and a higher genetic risk of obesity and high-BMI weight traits, which also appeared to share genetic risk with depression [18]. 

It must be noted that not all obese patients with depression (and vice-versa) fit the neuroinflammation subtype. It is possible to be metabolically healthy obese, where patients do not suffer from inflammation-based metabolic complications, and risk of depression. This was highlighted through identical twin studies carried out by Pietiläinen and colleagues in 2013[16]. And in the reciprocal risk relationship of obesity-associated depression and depression-associated obesity, representing a lesser risk than obesity, in underweight and overweight patients, implying a BMI ‘dose-response gradient’ [5]. 

Overall, the obesity and depression epidemic is not an unstoppable trend. Advances in Neuroscience, namely psychoneuroimmunology targeted research, recognises inflammation as an important mechanism in the vicious cycle between obesity and depression. New clinical research in this arena, discusses the ‘urgent need to reduce inflammation in overweight people with depression’, finding a 2.4 times more likelihood of clinically elevated levels of inflammation in this subtype, along with ‘depression significantly aggravating inflammation well beyond the expected effect of excess weight gain on inflammation’ [19].  

This raises the alarm for further investment in new, neurogenetic-psycho-nutritional interventions, alongside psychoneuroimmunology targeted research, that seek to break the cycle for at risk neuroinflammation subtypes. An example of such investment is ZOE based PREDICT research (Personalised Responses to Dietary Composition Trial). A series of the world’s largest nutritional science studies led in part by Geneticist and Epidemiologist Professor Tim Spector. 

The PREDICT studies question the longstanding ‘one size fits all’ paradigm, by looking to trial ‘precision nutrition, which may point to a complimentary endocrine-centric paradigm, in recognising that each individual’s endocrinal and metabolic responses vary in response to different foods. The studies ask, ‘how do macronutrients behave on their own, and in combinations of foods, and dietary patterns by individual? Factoring genetic as well as endocrinal glycaemic and metabolic individual differences in the population. 

In so doing, it likely confers greater benefit for vulnerable neuroinflammation subtypes, in treating each individual as unique [20]. Furthermore, PREDICT has highlighted that the inflammatory response is also highly variable amongst the general population, prompting the need for more in-depth profiling of variables such as genetics, gender, age, lifestyle and environment. Applying new statistical models seems critical, courtesy of computational neuroscience involving mathematical modelling, and the latest neuroimaging technology. 

It raises the question, would it be possible to potentially prototype inflammation itself, and its response to dietary changes across the varied population? Ultimately, these and other burgeoning studies, highlight the role of inflammation in disease, and as an important mechanism in the obesity-depression reciprocal relationship. And so areas for potential future treatments in bridging the gap between research in the lab and real-life, in an applied understanding of fat cells’ relationship to depression. 

 Author: Treesje Verlinden

This Article aims to present a unique viewpoint on existing problems, prevalent notions and fundamental concepts, on the specific topic of fat cells’ relationship with depression. Proposing and supporting new hypotheses, and discussing the implications of newly implemented innovations in neuroscience.

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