No abstract

Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.

Most actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding for the GR have been described. It is unclear to what extent the observed response variability is due to GR polymorphisms or to other factors. However, at least three polymorphisms seem to be associated with altered GC sensitivity and changes in body composition and metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to GCs, increased insulin response to DEX, a tendency towards lower bone mineral density, and increased body mass index (BMI). However, other reports found no associations with BMI. Another polymorphism, previously described as a BclI restriction fragment length polymorphism, recently was identified as a C 3 G nucleotide change. The G allele also was associated with increased sensitivity to GCs. In middle-aged subjects, the G allele of this BclI polymorphism was associated with increased abdominal obesity, while at older age, a lower BMI was found, accompanied by a tendency towards lower lean body mass. A third polymorphism consists of two linked, single-nucleotide mutations in codons 22 and 23, of which the second mutation results in an amino acid change from arginine (R) to lysine (K). In contrast to the other polymorphisms, this ER22/23EK polymorphism was associated with a relative resistance to GCs. In line with this, ER22/23EK carriers had lower total cholesterol and low-density lipoprotein cholesterol levels as well as lower fasting insulin concentrations and a better insulin sensitivity. C-reactive protein levels were lower in ER22/23EK carriers, as was found in a different population of elderly males. In accordance with this healthy metabolic profile, we found in this population a significantly better survival in ER22/23EK carriers after a 4-year follow-up. GCs also affect the brain. Although a certain level of cortisol is essential for proper brain functioning, excessive GC levels have been shown to negatively affect brain morphology and functions. At older age, we found that the risk of dementia and white matter lesions was lower in ER22/23EK carriers. GCs are also important in the regulation of body fat distribution. At young age, we observed sex-specific differences in body composition. Male ER22/23EK carriers were taller, had more muscle mass, and were stronger than noncarriers. In young females, ER22/23EK carriers had tendencies towards smaller waist and hip circumferences and lower body weight. Another polymorphism (TthIIII) was not associated with altered GC sensitivity. In conclusion, these polymorphisms in the GR gene may contribute considerably to the observed variability in GC sensitivity. As a result, they are associated with several differences in body composition and metabolic factors.

We characterized a BclI-RFLP (restriction fragment length polymorphism) of the GR gene as a C/G polymorphism in intron 2 of which the G-allele was associated with hypersensitivity to glucocorticoids. This resulted in a lower BMI in older individuals in general, while our study in elderly males suggests that the lower BMI is probably due to a greater loss of lean mass during the ageing process.