Chronic stress and obesity: a new view of "comfort food"

Abstract

The effects of adrenal corticosteroids on subsequent adrenocorticotropin secretion are complex. Acutely (within hours), glucocorticoids (GCs) directly inhibit further activity in the hypothalamo-pituitary-adrenal axis, but the chronic actions (across days) of these steroids on brain are directly excitatory. Chronically high concentrations of GCs act in three ways that are functionally congruent. (i) GCs increase the expression of corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala, a critical node in the emotional brain. CRF enables recruitment of a chronic stress-response network. (ii) GCs increase the salience of pleasurable or compulsive activities (ingesting sucrose, fat, and drugs, or wheel-running). This motivates ingestion of "comfort food." (iii) GCs act systemically to increase abdominal fat depots. This allows an increased signal of abdominal energy stores to inhibit catecholamines in the brainstem and CRF expression in hypothalamic neurons regulating adrenocorticotropin. Chronic stress, together with high GC concentrations, usually decreases body weight gain in rats; by contrast, in stressed or depressed humans chronic stress induces either increased comfort food intake and body weight gain or decreased intake and body weight loss. Comfort food ingestion that produces abdominal obesity, decreases CRF mRNA in the hypothalamus of rats. Depressed people who overeat have decreased cerebrospinal CRF, catecholamine concentrations, and hypothalamo-pituitary-adrenal activity. We propose that people eat comfort food in an attempt to reduce the activity in the chronic stress-response network with its attendant anxiety. These mechanisms, determined in rats, may explain some of the epidemic of obesity occurring in our society.

Fig. 1.

Models representing the acute and chronic effects of GC on function in the HPA axis. The canonical effects occur rapidly, within minutes to a few hours after stress; GCs act directly on brain and pituitary probably through nongenomic mechanisms. The new model requires ≈24 h, after elevation of GC into stress concentrations. Then, the direct action of GCs on brain is stimulatory, and the negative feedback inhibition of function in the HPA axis is a consequence of metabolic effects of GC increasing abdominal energy stores.

Fig. 2.

In rats exposed to a chronic stressor, high GC concentrations are required to stimulate ACTH responses to novel stimuli. Adrenalectomized rats were treated with B pellets and were maintained at room temperature (solid line, open symbol) or in cold for the next 5 days (dashed line, filled symbol). Blood was sampled in the morning within 1 min (Left) or 30 min after the onset of restraint (Right; ref. 3).

Fig. 3.

Minimal working model of the chronic stress-response network. This model is based on structures that exhibited increased numbers of c-Foslabeled cells in response to acute, novel restraint in rats with previous cold exposures compared to naive rats (6). PVThal, paraventricular nuclei of the thalamus; CeA, central nuclei of the amygdala; BNST, bed nuclei of the stria terminalis; NE, norepinephrine. Solid lines and arrows are stimulatory; dashed lines and open arrows are inhibitory.

Fig. 4.

B redistributes energy stores into intraabdominal sites and increases sucrose appetite. Adrenalectomized rats were replaced with a variety of doses of B and allowed to drink sucrose for a total of 9 days in a 15-day experiment (32). Significant linear regressions between B and the variable plotted are indicated by lines and r² values. Although high B concentrations strongly reduce both body weight gain and caloric efficiency, they increase both sucrose ingestion and mesenteric white adipose tissue (WAT) stores and have no effect on chow intake and s.c. WAT stores.

Fig. 5.

Both the amount of ingested sucrose and mesenteric WAT are significantly, negatively correlated with CRF mRNA in the PVN. All points are from adrenalectomized rats without B that were given either sucrose or saccharin. The sucrose data are from refs. and , and the mesenteric WAT results are from refs. and .

Fig. 6.

Minimal working model of the actions of B on metabolic feedback of CRF and ACTH secretion. In the presence of food intake and insulin secretion, B stimulates accretion of abdominal energy depots. By contrast, without adequate food intake and insulin secretion, there is loss of energy stores. A signal of abdominal energy stores (to date unidentified) acts to inhibit noradrenergic (A2) and adrenergic (C2) norepinephrine (NE)- or epinephrine (E)-synthesizing neurons in the nucleus of the tractus solitarius (NTS). Catecholaminergic neurons innervate all three CRF-containing structures, the central nuclei of the amygdala (CeA), the bed nuclei of the stria terminalis (BNST), and the hypothalamic PVN.

Fig. 7.

B increases salience of the pleasurable drink, saccharin. Sham-operated or adrenalectomized rats with varying B treatments were allowed to drink saccharin for 9 days in a 15-day experiment. The data shown represent drinking on the last day of the experiment (38).