Abnormal relationships between the neural response to high- and low-calorie foods and endogenous acylated ghrelin in women with active and weight-recovered anorexia nervosa

Abstract

Evidence contributing to the understanding of neurobiological mechanisms underlying appetite dysregulation in anorexia nervosa draws heavily on separate lines of research into neuroendocrine and neural circuitry functioning. In particular, studies consistently cite elevated ghrelin and abnormal activation patterns in homeostatic (hypothalamus) and hedonic (striatum, amygdala, insula) regions governing appetite. The current preliminary study examined the interaction of these systems, based on research demonstrating associations between circulating ghrelin levels and activity in these regions in healthy individuals. In a cross-sectional design, we studied 13 women with active anorexia nervosa (AN), 9 women weight-recovered from AN (AN-WR), and 12 healthy-weight control women using a food cue functional magnetic resonance imaging paradigm, with assessment of fasting levels of acylated ghrelin. Healthy-weight control women exhibited significant positive associations between fasting acylated ghrelin and activity in the right amygdala, hippocampus, insula, and orbitofrontal cortex in response to high-calorie foods, associations which were absent in the AN and AN-WR groups. Women with AN-WR demonstrated a negative relationship between ghrelin and activity in the left hippocampus in response to high-calorie foods, while women with AN showed a positive association between ghrelin and activity in the right orbitofrontal cortex in response to low-calorie foods. Findings suggest a breakdown in the interaction between ghrelin signaling and neural activity in relation to reward responsivity in AN, a phenomenon that may be further characterized using pharmacogenetic studies.

Toward valid and reliable brain imaging results in eating disorders

“…For example, in restrictive eating disorders such as anorexia nervosa, chronic starvation may lead to hypothalamic amenorrhea with hypoestrogenemia, low testosterone levels, hypercortisolemia, growth hormone resistance (high growth hormone, but low downstream IGF‐1 levels), and altered secretion of appetite‐regulating hormones (e.g., low anorexigenic hormones leptin and oxytocin; high orexigenic ghrelin [Culbert, Racine, & Klump, ; Misra & Klibanski, ] and AGRP [Merle et al, ]). While many hormonal alterations in response to low‐weight are adaptive (i.e., to stimulate food consumption and/or conserve limited resources) and resolve with weight restoration, evidence of seemingly paradoxical hormone levels in some cases (e.g., high levels of anorexigenic PYY) and persistent abnormalities after weight gain (e.g., in PYY [Misra et al, ; Nakahara et al, ; Pfluger et al, ]), ghrelin (Holsen, Lawson, Christensen, Klibanski, & Goldstein, ; Nakahara et al, ), oxytocin (Afinogenova et al, ), hypothalamic–pituitary–adrenal axis (e.g., cortisol) (Grinspoon et al, ; Lawson et al, ; Mayer et al, ) argue for a potential etiologic role versus scar or delayed recovery from chronic starvation, or effects of residual psychopathology (Misra & Klibanski, ). Endocrine changes, including reproductive dysfunction, activation of the hypothalamic–pituitary–adrenal axis, and differences in secretion of appetite‐regulating hormones, have also been demonstrated in other eating disorders, such as bulimia nervosa and binge‐eating disorder (Culbert et al, ; Poyastro Pinheiro et al, ).…”

“…While many hormonal alterations in response to low-weight are adaptive (i.e., to stimulate food consumption and/or FRANK ET AL. | 253 conserve limited resources) and resolve with weight restoration, evidence of seemingly paradoxical hormone levels in some cases (e.g., high levels of anorexigenic PYY) and persistent abnormalities after weight gain (e.g., in PYY [Misra et al, 2006;Nakahara et al, 2007;Pfluger et al, 2007]), ghrelin (Holsen, Lawson, Christensen, Klibanski, & Goldstein, 2014;Nakahara et al, 2007), oxytocin (Afinogenova et al, 2016), hypothalamic-pituitary-adrenal axis (e.g., cortisol) (Grinspoon et al, 2001;Lawson et al, 2013;Mayer et al, 2005) argue for a potential etiologic role versus scar or delayed recovery from chronic starvation, or effects of residual psychopathology (Misra & Klibanski, 2014).…”

Abnormal functional global and local brain connectivity in female patients with anorexia nervosa

“…Based on the clinical presentation, several functional neuroimaging studies have focused on the processing of food/taste and other appe titive stimuli. [4][5][6][7][8][9] Results suggest that patients may have an al tered sensitivity for sensory interoceptive and/or reward processes as well as an impaired awareness of homeostatic needs. 10 However, published reports revealed considerable inconsistencies, which may be explained by substantial vari ability among studies, including issues with task design, stimulus selection and varying cognitive abilities of the starv ing participants.…”

Reduced functional connectivity in the thalamo‐insular subnetwork in patients with acute anorexia nervosa

“…However, compared to other neuropsychiatric disorders, neuroimaging research in AN has only recently gained momentum. Existing studies, which are often limited by small sample sizes, have focused on executive functioning [Kullmann et al, ; Lock et al, ; Sato et al, ; Wierenga et al, ; Zastrow et al, ] or the processing of food/taste and other appetitive stimuli [Bischoff‐Grethe et al, ; Brooks et al, ; Holsen et al, ; Oberndorfer et al, ; Wagner et al, ]. Results suggest that patients may have an altered sensitivity for sensory‐interoceptive and/or reward processes as well as an impaired awareness of homeostatic needs [Kaye et al, ].…”