The appropriate utilisation, storage and conversion of nutrients in peripheral tissues, referred to as nutrient partitioning, is a fundamental process to adapt to nutritional and metabolic challenges ...and is thus critical for the maintenance of a healthy energy balance. Alterations in this process during nutrient excess can have deleterious effects on glucose and lipid homeostasis and contribute to the development of obesity and type 2 diabetes. Nutrient partitioning is a complex integrated process under the control of hormonal and neural signals. Neural control relies on the capacity of the brain to sense circulating metabolic signals and mount adaptive neuroendocrine and autonomic responses. This review aims to discuss the hypothalamic neurocircuits and molecular mechanisms controlling nutrient partitioning and their potential contribution to metabolic maladaptation and disease.
Obesity significantly elevates the odds of developing mood disorders. Chronic consumption of a saturated high-fat diet (HFD) elicits anxiodepressive behavior in a manner linked to metabolic ...dysfunction and neuroinflammation in mice. Dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) can improve both metabolic and mood impairments by relieving inflammation. Despite these findings, the effects of n-3 PUFA supplementation on energy homeostasis, anxiodepressive behavior, brain lipid composition, and gliosis in the diet-induced obese state are unclear.
Male C57Bl/6J mice were fed a saturated high-fat diet (HFD) or chow for 20 weeks. During the last 5 weeks mice received daily gavage ("supplementation") of fish oil (FO) enriched with equal amounts of docosahexaenoic (DHA) and eicosapentaenoic acid (EPA) or control corn oil. Food intake and body weight were measured throughout while additional metabolic parameters and anxiety- and despair-like behavior (elevated-plus maze, light-dark box, and forced swim tasks) were evaluated during the final week of supplementation. Forebrain lipid composition and markers of microglia activation and astrogliosis were assessed by gas chromatography-mass spectrometry and real-time PCR, respectively.
Five weeks of FO supplementation corrected glucose intolerance and attenuated hyperphagia in HFD-induced obese mice without affecting adipose mass. FO supplementation also defended against the anxiogenic and depressive-like effects of HFD. Brain lipids, particularly anti-inflammatory PUFA, were diminished by HFD, whereas FO restored levels beyond control values. Gene expression markers of brain reactive gliosis were supressed by FO.
Supplementing a saturated HFD with FO rich in EPA and DHA corrects glucose intolerance, inhibits food intake, suppresses anxiodepressive behaviors, enhances anti-inflammatory brain lipids, and dampens indices of brain gliosis in obese mice. Together, these findings support increasing dietary n-3 PUFA for the treatment of metabolic and mood disturbances associated with excess fat intake and obesity.
The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of ...running (“runner’s high”) are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food.
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•Dopamine-specific STAT3 knockout increases locomotion and voluntary running•Loss of STAT3 in dopamine neurons enhances the rewarding effects of running•Intra-VTA leptin inhibits running reward in a manner that relies on STAT3 signaling•Loss of STAT3 in dopamine neurons blunts mesolimbic dopamine overflow and function
Leptin can influence physical activity both positively and negatively. Fernandes et al. show that leptin signaling through STAT3 in dopamine neurons suppresses the rewarding effects of running (“runner’s high”) without affecting the anorectic actions of leptin or hedonic feeding.
Abstract
The beneficial effects of brown adipose tissue (BAT) on obesity and associated metabolic diseases are mediated through its capacity to dissipate energy as heat. While immune cells, such as ...tissue-resident macrophages, are known to influence adipose tissue homeostasis, relatively little is known about their contribution to BAT function. Here we report that neuropilin-1 (NRP1), a multiligand single-pass transmembrane receptor, is highly expressed in BAT-resident macrophages. During diet-induced obesity (DIO), myeloid-resident NRP1 influences interscapular BAT mass, and consequently vascular morphology, innervation density and ultimately core body temperature during cold exposure. Thus, NRP1-expressing myeloid cells contribute to the BAT homeostasis and potentially its thermogenic function in DIO.
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.
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.
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.
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.
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.
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.
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•Saturated HFD uniquely triggers metabolic impairments & depressive behavior.•Nucleus accumbens (NAc) inflammation & gliosis are distinct features of the saturated HFD.•Depressive behavior & NAc immune activation are mediated by IKKβ/NFκB signaling.•Inhibiting NAc IKKβ/NFκB suppresses compulsive sucrose seeking in mice fed the saturated HFD.
Mice are the most commonly used species in preclinical research on the pathophysiology of metabolic diseases. Although they are extremely useful for identifying pathways, mechanisms and genes ...regulating glucose and energy homeostasis, the specificities of the various mouse models and methodologies used to investigate a metabolic phenotype can have a profound impact on experimental results and their interpretation. This review aims to: (1) describe the most commonly used experimental tests to assess glucose and energy homeostasis in mice; (2) provide some guidelines regarding the design, analysis and interpretation of these tests, as well as for studies using genetic models; and (3) identify important caveats and confounding factors that must be taken into account in the interpretation of findings.
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.
The Fatty Acid Receptor GPR40 Plays a Role in Insulin Secretion In Vivo After High-Fat Feeding
Melkam Kebede 1 2 ,
Thierry Alquier 1 2 ,
Martin G. Latour 1 ,
Meriem Semache 1 ,
Caroline Tremblay 1 ...and
Vincent Poitout 1 2 3
1 Montréal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Canada
2 Department of Medicine, University of Montréal, Montréal, Canada
3 Department of Biochemistry, University of Montréal, Montréal, Canada
Corresponding author: Vincent Poitout, vincent.poitout{at}umontreal.ca
Abstract
OBJECTIVE— The G-protein–coupled receptor GPR40 is expressed in pancreatic β-cells and is activated by long-chain fatty acids. Gene deletion
studies have shown that GPR40 mediates, at least in part, fatty acid–amplification of glucose-induced insulin secretion (GSIS)
but is not implicated in GSIS itself. However, the role of GPR40 in the long-term effects of fatty acids on insulin secretion
remains controversial. This study aimed to test the hypothesis that GPR40 plays a role in insulin secretion after high-fat
feeding.
RESEARCH DESIGN AND METHODS— GPR40 knockout (KO) mice on a C57BL/6 background and their wild-type (WT) littermates were fed a high-fat diet (HFD) for 11
weeks. Glucose tolerance, insulin tolerance, and insulin secretion in response to glucose and Intralipid were assessed during
the course of the diet period.
RESULTS— GPR40 KO mice had fasting hyperglycemia. They became as obese, glucose intolerant, and insulin resistant as their WT littermates
given HFD and developed a similar degree of liver steatosis. Their fasting blood glucose levels increased earlier than those
of control mice during the course of the HFD. The remarkable increase in insulin secretory responses to intravenous glucose
and Intralipid seen in WT mice after HFD was of much lower magnitude in GPR40 KO mice.
CONCLUSIONS— GPR40 plays a role not only in fatty acid modulation of insulin secretion, but also in GSIS after high-fat feeding. These
observations raise doubts on the validity of a therapeutic approach based on GPR40 antagonism for the treatment of type 2
diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 16 June 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 30, 2008.
Received April 23, 2008.
DIABETES
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance and of the effects of leptin on food intake and fatty acid oxidation. Obesity is usually associated with resistance ...to the effects of leptin on food intake and body weight. To determine whether diet-induced obesity (DIO) impairs the AMPK response to leptin in muscle and/or hypothalamus, we fed FVB mice a high fat (55%) diet for 10–12 weeks. Leptin acutely decreased food intake by ∼30% in chow-fed mice. DIO mice tended to eat less, and leptin had no effect on food intake. Leptin decreased respiratory exchange ratio in chow-fed mice indicating increased fatty acid oxidation. Respiratory exchange ratio was low basally in high fat-fed mice, and leptin had no further effect. Leptin (3 mg/kg intraperitoneally) increased α2-AMPK activity 2-fold in muscle in chow-fed mice but not in DIO mice. Leptin decreased acetyl-CoA carboxylase activity 40% in muscle from chow-fed mice. In muscle from DIO mice, acetyl-CoA carboxylase activity was basally low, and leptin had no further effect. In paraventricular, arcuate, and medial hypothalamus of chow-fed mice, leptin inhibited α2-AMPK activity but not in DIO mice. In addition, leptin increased STAT3 phosphorylation 2-fold in arcuate of chow-fed mice, but this effect was attenuated because of elevated basal STAT3 phosphorylation in DIO mice. Thus, DIO in FVB mice alters α2-AMPK in muscle and hypothalamus and STAT3 in hypothalamus and impairs further effects of leptin on these signaling pathways. Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states.
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