Cecile Hryhorczuk

Metabolic disturbances connecting obesity and depression

Obesity markedly increases the odds of developing depression. Depressed mood not only impairs motivation, quality of life and overall functioning but also increases the risks of obesity complications. Abdominal obesity is a better predictor of depression and anxiety risk than overall adipose mass. A growing amount of research suggests that metabolic abnormalities stemming from central obesity that lead to metabolic disease may also be responsible for the increased incidence of depression in obesity. As reviewed here, a higher mass of dysfunctional adipose tissue is associated with several metabolic disturbances that are either directly or indirectly implicated in the control of emotions and mood. To better comprehend the development of depression in obesity, this review pulls together select findings addressing the link between adiposity, diet and negative emotional states and discusses the evidence that alterations in glucocorticoids, adipose-derived hormones, insulin and inflammatory signaling that are characteristic of central obesity may be involved.

Dampened Mesolimbic Dopamine Function and Signaling by Saturated but not Monounsaturated Dietary Lipids

Overconsumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared with low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain, and plasma levels of leptin, insulin, and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor-mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes.

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

Background: Hypothalamic long-chain fatty acids (LCFA) and glucose are critical for energy balance, but it is not known if their metabolism is coupled. Results: Glucose regulates hypothalamic metabolism of palmitate via AMP-activated kinase. Conclusion: Glucose and LCFA metabolism is coupled in a cell-type and LCFA-dependent manner. Significance: This is the first evidence for glucose regulation of LCFA metabolic fate in the hypothalamus. Hypothalamic controls of energy balance rely on the detection of circulating nutrients such as glucose and long-chain fatty acids (LCFA) by the mediobasal hypothalamus (MBH). LCFA metabolism in the MBH plays a key role in the control of food intake and glucose homeostasis, yet it is not known if glucose regulates LCFA oxidation and esterification in the MBH and, if so, which hypothalamic cell type(s) and intracellular signaling mechanisms are involved. The aim of this study was to determine the impact of glucose on LCFA metabolism, assess the role of AMP-activated Kinase (AMPK), and to establish if changes in LCFA metabolism and its regulation by glucose vary as a function of the kind of LCFA, cell type, and brain region. We show that glucose inhibits palmitate oxidation via AMPK in hypothalamic neuronal cell lines, primary hypothalamic astrocyte cultures, and MBH slices ex vivo but not in cortical astrocytes and slice preparations. In contrast, oleate oxidation was not affected by glucose or AMPK inhibition in MBH slices. In addition, our results show that glucose increases palmitate, but not oleate, esterification into neutral lipids in neurons and MBH slices but not in hypothalamic astrocytes. These findings reveal for the first time the metabolic fate of different LCFA in the MBH, demonstrate AMPK-dependent glucose regulation of LCFA oxidation in both astrocytes and neurons, and establish metabolic coupling of glucose and LCFA as a distinguishing feature of hypothalamic nuclei critical for the control of energy balance.

Progressive-ratio Responding for Palatable High-fat and High-sugar Food in Mice

Foods that are rich in fat and sugar significantly contribute to over-eating and escalating rates of obesity. The consumption of palatable foods can produce a rewarding effect that strengthens action-outcome associations and reinforces future behavior directed at obtaining these foods. Increasing evidence that the rewarding effects of energy-dense foods play a profound role in overeating and the development of obesity has heightened interest in studying the genes, molecules and neural circuitry that modulate food reward. The rewarding impact of different stimuli can be studied by measuring the willingness to work to obtain them, such as in operant conditioning tasks. Operant models of food reward measure acquired and voluntary behavioral responses that are directed at obtaining food. A commonly used measure of reward strength is an operant procedure known as the progressive ratio (PR) schedule of reinforcement. In the PR task, the subject is required to make an increasing number of operant responses for each successive reward. The pioneering study of Hodos (1961) demonstrated that the number of responses made to obtain the last reward, termed the breakpoint, serves as an index of reward strength. While operant procedures that measure changes in response rate alone cannot separate changes in reward strength from alterations in performance capacity, the breakpoint derived from the PR schedule is a well-validated measure of the rewarding effects of food. The PR task has been used extensively to assess the rewarding impact of drugs of abuse and food in rats (e.g., 6-8), but to a lesser extent in mice. The increased use of genetically engineered mice and diet-induced obese mouse models has heightened demands for behavioral measures of food reward in mice. In the present article we detail the materials and procedures used to train mice to respond (lever-press) for a high-fat and high-sugar food pellets on a PR schedule of reinforcement. We show that breakpoint response thresholds increase following acute food deprivation and decrease with peripheral administration of the anorectic hormone leptin and thereby validate the use of this food-operant paradigm in mice.

Nutritional controls of food reward.

The propensity to select and consume palatable nutrients is strongly influenced by the rewarding effects of food. Neural processes integrating reward, emotional states and decision-making can supersede satiety signals to promote excessive caloric intake and weight gain. While nutritional habits are influenced by reward-based neural mechanisms, nutrition and its impact on energy metabolism, in turn, plays an important role in the control of food reward. Feeding modulates the release of metabolic hormones that have an important influence on central controls of appetite. Nutrients themselves are also an essential source of energy fuel, while serving as key metabolites and acting as signalling molecules in the neural pathways that control feeding and food reward. Along these lines, this review discusses the impact of nutritionally regulated hormones and select macronutrients on the behavioural and neural processes underlying the rewarding effects of food.

Dopamine signalling adaptations by prolonged high-fat feeding

Prolonged high-fat feeding modulates dopamine tone in mesolimbic and nigrostriatal pathways, an outcome that is proposed to influence food-motivated behaviour and reward sensitivity. Study of the impact of chronic high-fat feeding on dopamine signalling and behavioural function in rodents has yielded highly variable results. Here we attempt to shed light on this literature by cataloguing findings according to the degree of body weight gain. A pattern emerges whereby high-fat feeding leading to full-scale obesity is largely reported to inhibit dopamine availability and release. In contrast, impairments in dopamine transporter function are apparent in conditions of little to considerable weight gain. Identification of the mechanisms underlying the neurobehavioral adaptations to high-fat diet would benefit from greater investigation of associated metabolic consequences.

Central Agonism of GPR120 Acutely Inhibits Food Intake and Food Reward and Chronically Suppresses Anxiety-Like Behavior in Mice

Background: GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the antiinflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids. Increasing central ω-3 polyunsaturated fatty acid levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120, its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward, and anxiety-like behavior. Methods: Male C57Bl/6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1 µM) or continuous 2-week infusion (1 µM/d; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry), and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test. Results: GPR120 agonist injections substantially reduced chow intake during 4 hours postinjection, suppressed the rewarding effects of high-fat/-sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behavior in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure, and body weight on a high-fat diet. Conclusion: Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 polyunsaturated fatty acids to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety.

Saturated high-fat feeding independent of obesity alters hypothalamus-pituitary-adrenal axis function but not anxiety-like behaviour.

Overconsumption of dietary fat can elicit impairments in emotional processes and the response to stress. While excess dietary lipids have been shown to alter hypothalamus-pituitary-adrenal (HPA) axis function and promote anxiety-like behaviour, it is not known if such changes rely on elevated body weight and if these effects are specific to the type of dietary fat. The objective of this study was to investigate the effect of a saturated and a monounsaturated high-fat diet (HFD) on HPA axis function and anxiety-like behaviour in rats. Biochemical, metabolic and behavioural responses were evaluated following eight weeks on one of three diets: (1) a monounsaturated HFD (50%kcal olive oil), (2) a saturated HFD (50%kcal palm oil), or (3) a control low-fat diet. Weight gain was similar across the three diets while visceral fat mass was elevated by the two HFDs. The saturated HFD had specific actions to increase peak plasma levels of corticosterone and tumour-necrosis-factor-alpha and suppress mRNA expression of glucocorticoid and mineralocorticoid receptors, corticotropin-releasing hormone and 11β-hydroxysteroid dehydrogenase-1 in the paraventricular nucleus of the hypothalamus. Both HFDs enhanced the corticosterone-suppressing response to dexamethasone administration without affecting the physiological response to a restraint stress and failed to increase anxiety-like behaviour as measured in the elevated-plus maze and open field tests. These findings demonstrate that prolonged intake of saturated fat, without added weight gain, increases CORT and modulates central HPA feedback processes. That saturated HFD failed to affect anxiety-like behaviour can suggest that the anxiogenic effects of prolonged high-fat feeding may rely on more pronounced metabolic dysfunction.

Oleic Acid in the Ventral Tegmental Area Inhibits Feeding, Food Reward, and Dopamine Tone

Long-chain fatty acids (FAs) act centrally to decrease food intake and hepatic glucose production and alter hypothalamic neuronal activity in a manner that depends on FA type and cellular transport proteins. However, it is not known whether FAs are sensed by ventral tegmental area (VTA) dopamine (DA) neurons to control food-motivated behavior and DA neurotransmission. We investigated the impact of the monounsaturated FA oleate in the VTA on feeding, locomotion, food reward, and DA neuronal activity and DA neuron expression of FA-handling proteins and FA uptake. A single intra-VTA injection of oleate, but not of the saturated FA palmitate, decreased food intake and increased locomotor activity. Furthermore, intra-VTA oleate blunted the rewarding effects of high-fat/sugar food in an operant task and inhibited DA neuronal firing. Using sorted DA neuron preparations from TH-eGFP mice we found that DA neurons express FA transporter and binding proteins, and are capable of intracellular transport of long-chain FA. Finally, we demonstrate that a transporter blocker attenuates FA uptake into DA neurons and blocks the effects of intra-VTA oleate to decrease food-seeking and DA neuronal activity. Together, these results suggest that DA neurons detect FA and that oleate has actions in the VTA to suppress DA neuronal activity and food seeking following cellular incorporation. These findings highlight the capacity of DA neurons to act as metabolic sensors by responding not only to hormones but also to FA nutrient signals to modulate food-directed behavior.

Nucleus accumbens inflammation mediates anxiodepressive behavior and compulsive sucrose seeking elicited by saturated dietary fat

Objective The incidence of depression is significantly compounded by obesity. Obesity arising from excessive intake of high-fat food provokes anxiodepressive behavior and elicits molecular adaptations in the nucleus accumbens (NAc), a region well-implicated in the hedonic deficits associated with depression and in the control of food-motivated behavior. To determine the etiology of diet-induced depression, we studied the impact of different dietary lipids on anxiodepressive behavior and metabolic and immune outcomes and the contribution of NAc immune activity. Methods Adult C57Bl/6 mice were subjected to isocaloric high-fat/high-sucrose diets (HFD), enriched in either saturated or monounsaturated fat, or a control low-fat diet (LFD). Metabolic responses, anxiodepressive behavior, and plasma and NAc inflammatory markers were assessed after 12 weeks. In separate experiments, an adenoviral construct inhibiting IKKβ, an upstream component of the nuclear factor kappa-b (NFkB) pathway, was a priori injected into the NAc. Results Both HFDs resulted in obesity and hyperleptinemia; however, the saturated HFD uniquely triggered anxiety-like behavior, behavioral despair, hyperinsulinemia, glucose intolerance, peripheral inflammation, and multiple pro-inflammatory signs in the NAc, including reactive gliosis, increased expression of cytokines, antigen-presenting markers and NFкB transcriptional activity. Selective NAc IKKβ inhibition reversed the upregulated expression of inflammatory markers, prevented anxiodepressive behavior and blunted compulsive sucrose-seeking in mice fed the saturated HFD. Conclusions Metabolic inflammation and NFкB-mediated neuroinflammatory responses in the NAc contribute to the expression of anxiodepressive behavior and heightened food cravings caused by a diet high in saturated fat and sugar.