Higher body mass index is linked to altered hypothalamic microstructure.

Animal studies suggest that obesity-related diets induce structural changes in the hypothalamus, a key brain area involved in energy homeostasis. Whether this translates to humans is however largely unknown. Using a novel multimodal approach with manual segmentation, we here show that a higher body mass index (BMI) selectively predicted higher proton diffusivity within the hypothalamus, indicative of compromised microstructure in the underlying tissue, in a well-characterized population-based cohort (n1 = 338, 48% females, age 21-78 years, BMI 18-43 kg/m²). Results were independent from confounders and confirmed in another independent sample (n2 = 236). In addition, while hypothalamic volume was not associated with obesity, we identified a sexual dimorphism and larger hypothalamic volumes in the left compared to the right hemisphere. Using two large samples of the general population, we showed that a higher BMI specifically relates to altered microstructure in the hypothalamus, independent from confounders such as age, sex and obesity-associated co-morbidities. This points to persisting microstructural changes in a key regulatory area of energy homeostasis occurring with excessive weight. Our findings may help to better understand the pathomechanisms of obesity and other eating-related disorders.

Sex differences in serotonin-hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight.

BACKGROUND/OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress related to weight remain largely unknown. PARTICIPANTS/METHODS: Here we combined positron emission tomography, using the serotonin transporter (5-HTT) radiotracer [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, with functional connectivity magnetic resonance imaging, the Beck Depression Inventory (BDI-II) and the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite) to investigate the role of central serotonin in the severity of depression (BDI-II), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a group of lean to morbidly obese individuals (n=28), we found sex differences in the 5-HTT availability-related connectivity of the hypothalamus. Males (n=11) presented a strengthened connectivity to the lateral orbitofrontal cortex, whereas in females (n=17) we found strengethened projections to the ventral striatum. Both regions are known as reward regions involved in mediating the emotional response to food. Their resting-state activity correlated positively to the body mass index (BMI) and IWQOL-Lite scores, suggesting that each region in both sexes also underpins a diminished sense of emotional well-being with body weight. Contrarily to males, we found that in females also the BDI-II positively correlated with the BMI and by trend with the activity in ventral striatum, suggesting that in females an increased body weight may convey to other mood dimensions than those weight-related ones included in the IWQOL-Lite. CONCLUSIONS: This study suggests sex differences in serotonin-hypothalamic connections to brain regions of the reward circuitry underpinning a diminished sense of emotional well-being with an increasing body weight.

Adipocyte fatty acid-binding protein is released from adipocytes by a non-conventional mechanism.

Adipocyte fatty acid-binding protein (AFABP) is an adipokine, which induces insulin resistance. However, AFABP does not possess any secretion-directed signals and the mechanisms for AFABP release have not been thoroughly assessed so far. In the current study, mechanisms for AFABP secretion were elucidated in 3T3-L1 adipocytes in vitro in the presence or absence of hormonal stimulation, calcium ionophore and secretion inhibitors by cell fractionation experiments, immunoblotting and ELISAs. We demonstrate that AFABP secretion is upregulated during adipocyte differentiation. AFABP secretion is not influenced by treatment with protein secretion inhibitors that block vesicular traffic at the endoplasmic reticulum and the Golgi apparatus. AFABP is secreted partially by adipocyte-derived microvesicles (ADMs), an established mechanism for unconventional secretion from adipocytes. Both total and ADM-secreted AFABP are downregulated by insulin and upregulated by the calcium ionophore ionomycin. Furthermore, murine RAW 264.7 macrophages secrete AFABP and AFABP release from these cells is upregulated by lipopolysaccharide treatment. Taken together, these results suggest that AFABP is actively released by unconventional mechanisms and by ADMs from 3T3-L1 adipocytes. Furthermore, AFABP secretion from fat cells is regulated by insulin and intracellular calcium.

Neural correlates of the volitional regulation of the desire for food.

OBJECTIVE: In this study, we investigate the brain mechanisms of the conscious regulation of the desire for food using functional magnetic resonance imaging. Further, we examine associations between hemodynamic responses and participants' cognitive restraint of eating (CRE), as well as their susceptibility to uncontrolled eating. SUBJECTS: Seventeen non-vegetarian, right-handed, female Caucasian participants (age: 20-30 years, mean 25.3 years±3.1 s.d.; BMI: 20.2-31.2 kg m(-2), mean 25.1±3.5 s.d.). MEASUREMENTS: During scanning, our participants viewed pictures of food items they had pre-rated according to tastiness and healthiness. Participants were either allowed to admit to the desire for the food (ADMIT) or they were instructed to downregulate their desire using a cognitive reappraisal strategy, that is, thinking of negative long-term health-related and social consequences (REGULATE). RESULTS: Comparing the hemodynamic responses of the REGULATE with the ADMIT condition, we observed robust activation in the dorsolateral prefrontal cortex (DLPFC), the pre-supplementary motor area, the inferior frontal gyrus (IFG), the dorsal striatum (DS), the bilateral orbitofrontal cortex (OFC), the anterior insula and the temporo-parietal junction (TPJ). Activation in the DLPFC and the DS strongly correlated with the degree of dietary restraint under both conditions. CONCLUSION: Cortical activation in the DLPFC, the pre-supplementary motor area and the inferior frontal gyrus (IFG) are known to underpin top-down control, inhibition of learned associations and pre-potent responses. The observed hemodynamic responses in the lateral OFC, the DS, the anterior insula and the TPJ support the notion of reward valuation and integration, interoceptive awareness, and self-reflection as key processes during active regulation of desire for food. In conclusion, an active reappraisal of unhealthy food recruits the brain's valuation system in combination with prefrontal cognitive control areas associated with response inhibition. The correlations between brain responses and CRE suggest that individuals with increased cognitive restraint show an automatic predisposition to regulate the hedonic aspects of food stimuli. This cognitive control might be necessary to counterbalance a lack of homeostatic mechanisms.