Julian G. Mercer

“Eating addiction”, rather than “food addiction”, better captures addictive-like eating behavior

Food addiction has become a focus of interest for researchers attempting to explain certain processes and/or behaviors that may contribute to the development of obesity. Although the scientific discussion on food addiction is in its nascent stage, it has potentially important implications for treatment and prevention strategies. As such, it is important to critically reflect on the appropriateness of the term food addiction, which combines the concepts of substance-based and behavioral addiction. The currently available evidence for a substance-based food addiction is poor, partly because systematic clinical and translational studies are still at an early stage. We do however view both animal and existing human data as consistent with the existence of addictive eating behavior. Accordingly, we stress that similar to other behaviors eating can become an addiction in thus predisposed individuals under specific environmental circumstances. Here, we introduce current diagnostic and neurobiological concepts of substance-related and non-substance-related addictive disorders, and highlight the similarities and dissimilarities between addiction and overeating. We conclude that food addiction is a misnomer because of the ambiguous connotation of a substance-related phenomenon. We instead propose the term eating addiction to underscore the behavioral addiction to eating; future research should attempt to define the diagnostic criteria for an eating addiction, for which DSM-5 now offers an umbrella via the introduction on Non-Substance-Related Disorders within the category Substance-Related and Addictive Disorders.

Ontogeny of the expression of leptin and its receptor in the murine fetus and placenta.

Leptin is a 167-amino acid protein that is secreted from adipose cells and expressed in placental tissues. It is important nutritionally in the regulation of energy balance, but also has other functions such as a role in reproduction. To investigate the function of the leptin system in fetal development we examined, primarily by in-situ hybridization and immunohistochemistry, the expression (both mRNA and protein) of leptin and its receptor (including the signalling splice variant) in tissues from 11.5, 13.5, 16.5 and 18.5 d postcoitus murine fetuses and associated placentas. We detected leptin mRNA (at low levels) and protein predominantly in the cytotrophoblasts of the labyrinth part of the placenta, an area of nutrient exchange between the developing fetus and the placenta, and in the trophoblast giant cells situated in the junctional zone at the maternal interface. In addition, leptin was strongly expressed in the fetal cartilage-bone and at a lower level in the hair follicles, heart, and liver of the murine fetus at differing stages of development. The leptin receptor, including the signalling splice variant, was also identified in specific fetal tissues. The physiological importance of expression of both leptin and the leptin receptor (OB-R and OB-Rb) in the placenta remains to be determined. In addition, the high levels of expression of leptin and its receptor in discrete areas of the murine fetus suggest that leptin has a critical role in fetal development.

Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat

In the adult brain, leptin regulates energy homeostasis primarily via hypothalamic circuitry that affects food intake and energy expenditure. Evidence from rodent models has demonstrated that during early postnatal life, leptin is relatively ineffective in modulating these pathways, despite the high circulating levels and the presence of leptin receptors within the central nervous system. Furthermore, in recent years, a neurotrophic role for leptin in the establishment of energy balance circuits has emerged. The precise way in which leptin exerts these effects, and the site of leptin action, is unclear. To provide a detailed description of the development of energy balance systems in the postnatal rat in relation to leptin concentrations during this time, endogenous leptin levels were measured, along with gene expression of leptin receptors and energy balance neuropeptides in the medial basal hypothalamus, using in situ hybridization. Expression of leptin receptors and both orexigenic and anorexigenic neuropeptides increased in the arcuate nucleus during the early postnatal period. At postnatal day 4 (P4), we detected dense leptin receptor expression in ependymal cells of the third ventricle (3V), which showed a dramatic reduction over the first postnatal weeks, coinciding with marked morphological changes in this region. An acute leptin challenge robustly induced suppressor of cytokine signaling-3 expression in the 3V of P4 but not P14 animals, revealing a clear change in the location of leptin action over this period. These findings suggest that the neurotrophic actions of leptin may involve signaling at the 3V during a restricted period of postnatal development.

Programming of hypothalamic neuropeptide gene expression in rats by maternal dietary protein content during pregnancy and lactation.

Epidemiological studies show a link between low birthweight and increased obesity. In contrast, slow growth during the lactation period reduces obesity risk. The present study investigates the potential underlying mechanisms of these observations. Rats were established as follows: (i) control animals [offspring of control dams fed a 20% (w/v) protein diet], (ii) recuperated animals [offspring of dams fed an isocaloric low-protein (8%, w/v) diet during pregnancy and nursed by control dams], and (iii) postnatal low protein animals (offspring of control dams nursed by low-protein-fed dams). Serum and brains were collected from fed and fasted animals at weaning. Expression of hypothalamic energy balance genes was assessed using in situ hybridization. Recuperated pups were smaller at birth, but caught up with controls by day 21 and gained more weight than controls between weaning and 12 weeks of age (P<0.05). At 21 days, they were hypoleptinaemic compared with controls in the fed state, with generally comparable hypothalamic gene expression. Postnatal low protein offspring had significantly lower body weights than controls at weaning and 12 weeks of age (P<0.001). At 21 days, they were hypoglycaemic, hypoinsulinaemic and hypoleptinaemic. Leptin receptor gene expression in the arcuate nucleus was increased in postnatal low protein animals compared with controls. Consistent with hypoleptinaemia, hypothalamic gene expression for the orexigenic neuropeptides NPY (neuropeptide Y) and AgRP (Agouti-related peptide) was increased, and that for the anorexigenic neuropeptides POMC (pro-opiomelanocortin) and CART (cocaine- and amphetamine-regulated transcript) was decreased. These results suggest that the early nutritional environment can affect the development of energy balance circuits and consequently obesity risk.

Hypothalamic ventricular ependymal thyroid hormone deiodinases are an important element of circannual timing in the Siberian hamster (Phodopus sungorus).

Exposure to short days (SD) induces profound changes in the physiology and behaviour of Siberian hamsters, including gonadal regression and up to 30% loss in body weight. In a continuous SD environment after approximately 20 weeks, Siberian hamsters spontaneously revert to a long day (LD) phenotype, a phenomenon referred to as the photorefractory response. Previously we have identified a number of genes that are regulated by short photoperiod in the neuropil and ventricular ependymal (VE) cells of the hypothalamus, although their importance and contribution to photoperiod induced physiology is unclear. In this refractory model we hypothesised that the return to LD physiology involves reversal of SD expression levels of key hypothalamic genes to their LD values and thereby implicate genes required for LD physiology. Male Siberian hamsters were kept in either LD or SD for up to 39 weeks during which time SD hamster body weight decreased before increasing, after more than 20 weeks, back to LD values. Brain tissue was collected between 14 and 39 weeks for in situ hybridization to determine hypothalamic gene expression. In VE cells lining the third ventricle, expression of nestin, vimentin, Crbp1 and Gpr50 were down-regulated at 18 weeks in SD photoperiod, but expression was not restored to the LD level in photorefractory hamsters. Dio2, Mct8 and Tsh-r expression were altered by SD photoperiod and were fully restored, or even exceeded values found in LD hamsters in the refractory state. In hypothalamic nuclei, expression of Srif and Mc3r mRNAs was altered at 18 weeks in SD, but were similar to LD expression values in photorefractory hamsters. We conclude that in refractory hamsters not all VE cell functions are required to establish LD physiology. However, thyroid hormone signalling from ependymal cells and reversal of neuronal gene expression appear to be essential for the SD refractory response.

Diurnal profiles of hypothalamic energy balance gene expression with photoperiod manipulation in the Siberian hamster, Phodopus sungorus

Hypothalamic energy balance genes have been examined in the context of seasonal body weight regulation in the Siberian hamster. Most of these long photoperiod (LD)/short photoperiod (SD) comparisons have been of tissues collected at a single point in the light-dark cycle. We examined the diurnal expression profile of hypothalamic genes in hamsters killed at 3-h intervals throughout the light-dark cycle after housing in LD or SD for 12 wk. Gene expression of neuropeptide Y, agouti-related peptide, proopiomelanocortin, cocaine- and amphetamine-regulated transcript, long-form leptin receptor, suppressor of cytokine signaling-3, melanocortin-3 receptor, melanocortin-4 receptor, and the clock gene Per1 as control were measured by in situ hybridization in hypothalamic nuclei. Effects of photoperiod on gene expression and leptin levels were generally consistent with previous reports. A clear diurnal variation was observed for Per1 in the suprachiasmatic nucleus in both photoperiods. Temporal effects on expression of energy balance genes were restricted to long-form leptin receptor in the arcuate nucleus and ventromedial nucleus, where similar diurnal expression profiles were observed, and melanocortin-4 receptor in the paraventricular nucleus; these effects were only observed in LD hamsters. There was no variation in serum leptin concentration. The 24-h profiles of hypothalamic energy balance gene expression broadly confirm photoperiodic differences that were observed previously, based on single time point comparisons, support the growing consensus that these genes have a limited role in seasonal body weight regulation, and further suggest limited involvement in daily rhythms of food intake.

Hypothalamic NPY and CRF gene expression in the food-deprived Syrian hamster

Because the Syrian hamster, Mesocricetus auratus, does not increase food intake in response to food deprivation, we investigated whether hypothalamic NPY gene expression in this species was sensitive to this imposed state of negative energy balance. In the rat, food deprivation for 48 h resulted in a 150% increase in total preproNPY gene expression in the arcuate nucleus of the hypothalamus (ARC). NPY gene expression in food-deprived Syrian hamsters did not differ significantly from that of ad lib-fed controls, although there was a trend towards increased mRNA levels in the fasted animals. However, food deprivation for 48 h was associated with a rise in preproCRF mRNA in the paraventricular nucleus of the hypothalamus (PVN) of 80-g, but not 150-g, hamsters. The expected reductions in plasma insulin accompanied food deprivation in the Syrian hamster, but cortisol titre was only elevated in the lower body weight group. NPY gene expression in the Syrian hamster appeared, however, to be sensitive to glucocorticoids; daily administration for 28 days of the synthetic glucocorticoid, dexamethasone, increased ARC NPY mRNA levels by 43%. The response of NPYergic and other hypothalamic neuropeptide systems to food deprivation, and the involvement of neuroendocrine substrates in energy homeostasis, may vary between species.

Postnatal development of hypothalamic leptin receptors.

The hormone, leptin, plays a key role in the regulation of energy balance and neuroendocrine function, as well as modulating a range of other physiological systems from immunity to cognition. In the adult brain, leptin regulates food intake and energy expenditure primarily via the hypothalamus. In addition to these well-defined actions in adult life, there is increasing evidence for a role of leptin during development. Leptin receptors are widely expressed in the developing brain from an early stage, and leptin is known to have profound effects on the proliferation, maintenance, and differentiation of neuronal and glial cells. During the early postnatal period, in both rats and mice, there is a surge in circulating leptin concentrations. Despite this elevation in leptin, neonates maintain a high level of food intake, and both feeding behavior and metabolic responses to exogenous leptin administration are absent until around the time of weaning. However, it is during this period that direct neurotrophic actions of leptin have been demonstrated, with leptin promoting neurite outgrowth and the establishment of hypothalamic circuitry. Exactly how leptin exerts these effects remains unknown, but changes in the distribution of hypothalamic leptin receptors during this period may, at least in part, underlie these age-specific effects of leptin.

Dietary Factors Affect Food Reward and Motivation to Eat

The propensity to indulge in unhealthy eating and overconsumption of palatable food is a crucial determinant in the rising prevalence of obesity in today’s society. The tendency to consume palatable foods in quantities that exceed energy requirements has been linked to an addiction-like process. Although the existence of ‘food addiction’ has not been conclusively proven, evidence points to alterations in the brain reward circuitry induced by overconsumption of palatable foods that are similar to those seen in drug addiction. The diet-induced obesity paradigm is a common procedure to replicate features of human obesity in rodents. Here we review data on the effect of various obesogenic diets (high-fat, Ensure™, cafeteria type, sucrose) on the extent of leptin resistance, hypothalamic-neuropeptidergic adaptations and changes in feeding behavior. We also discuss to what extent such diets and properties such as macronutrient composition, physical structure, sensory stimuli, and post-ingestive effects influence the brain-reward pathways. Understanding the interaction between individual components of diets, feeding patterns, and brain reward pathways could facilitate the design of diets that limit overconsumption and prevent weight gain.

A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

BACKGROUNDnThe thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms.nnnMETHODSnSprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA.nnnRESULTSnPost mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (± 1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic ventricular ependymal layer and differentially expressed in animal models of long- and short-term body weight regulation.nnnCONCLUSIONnThis study identified genes regulated by T3 in the hypothalamus, a key area of the brain involved in homeostasis and neuroendocrine functions. These include genes hitherto not known to be regulated by thyroid status.