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Objectives Ambient temperature impinges on energy metabolism in a body size dependent manner. This has implications for the housing temperature at which mice are best compared to humans. In 2013, we suggested that, for comparative studies, solitary mice are best housed at 23–25 °C, because this is 3–5 °C below the mouse thermoneutral zone and humans routinely live 3–5 °C below thermoneutrality, and because this generates a ratio of DEE to BMR of 1.6–1.9, mimicking the ratio found in free-living humans. Methods Recently, Fischer et al. (2017) challenged this estimate. By studying mice at 21 °C and at 30 °C (but notably not at 23–25 °C) they concluded that 30 °C is the optimal housing temperature. Here, we measured energy metabolism of C57BL/6 mice over a range of temperatures, between 21.4 °C and 30.2 °C. Results We observed a ratio of DEE to BMR of 1.7 at 27.6 °C and of 1.8 at 25.5 °C, suggesting that this is the best temperature range for housing C57BL/6 mice to mimic human thermal relations. We used a 24 min average to calculate the ratio, similar to that used in human studies, while the ratio calculated by Fisher et al. dependent on short, transient metabolic declines. Conclusion We concur with Fisher et al. and others that 21 °C is too cool, but we continue to suggest that 30 °C is too warm. We support this with other data. Finally, to mimic living environments of all humans, and not just those in controlled Western environments, mouse experimentation at various temperatures is likely required., Graphical abstract Image 1, Highlights • Translation from mice to man is best done at comparable metabolic conditions. • ‘Western’ humans metabolize at 1.7 to 1.8x BMR and are below thermoneutrality. • Thermoneutrality of solitary housed C57BL/6 laboratory mice commences above 28 °C. • 1.7x - 1.8x BMR for solitary housed C57BL/6 lab mice is between 25.5 °C - 27.6 °C. • Neither 21 °C nor 30 °C are suitable housing temperatures for translation.

Objective Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined. Methods We studied the mechanisms linking GCG action to acute increases in oxygen consumption using wildtype (WT), Ucp1−/− and Fgf21−/− mice. The importance of basal GCGR expression within the Myf5+ domain for control of body weight, adiposity, glucose and lipid metabolism, food intake, and energy expenditure was examined in GcgrBAT−/− mice housed at room temperature or 4 °C, fed a regular chow diet (RCD) or after a prolonged exposure to high fat diet (HFD). Results Acute GCG administration induced lipolysis and increased the expression of thermogenic genes in BAT cells, whereas knockdown of Gcgr reduced expression of genes related to thermogenesis. GCG increased energy expenditure (measured by oxygen consumption) both in vivo in WT mice and ex vivo in BAT and liver explants. GCG also increased acute energy expenditure in Ucp1−/− mice, but these actions were partially blunted in Ffg21−/− mice. However, acute GCG administration also robustly increased oxygen consumption in GcgrBAT−/− mice. Moreover, body weight, glycemia, lipid metabolism, body temperature, food intake, activity, energy expenditure and adipose tissue gene expression profiles were normal in GcgrBAT−/− mice, either on RCD or HFD, whether studied at room temperature, or chronically housed at 4 °C. Conclusions Exogenous GCG increases oxygen consumption in mice, also evident both in liver and BAT explants ex vivo, through UCP1-independent, FGF21-dependent pathways. Nevertheless, GCGR signaling within BAT is not physiologically essential for control of body weight, whole body energy expenditure, glucose homeostasis, or the adaptive metabolic response to cold or prolonged exposure to an energy dense diet., Graphical abstract Image 1, Highlights • A functional glucagon receptor is expressed in brown adipose tissue and BAT cells. • Glucagon increases energy expenditure in mice, as well as in liver and BAT. • Glucagon increases whole body energy expenditure through FGF21-dependent and BAT glucagon receptor-independent pathways. • Loss of the BAT glucagon receptor does not impair glucose or energy homeostasis in mice.

Objective To improve understanding of mouse energy homeostasis and its applicability to humans, we quantitated the effects of housing density on mouse thermal physiology in both sexes. Methods Littermate wild type and Brs3-null mice were single- or group- (three per cage) housed and studied by indirect calorimetry with continuous measurement of core body temperature, energy expenditure, physical activity, and food intake. Results At 23 °C, below thermoneutrality, single-housed males had a lower body temperature and unchanged metabolic rate compared to group-housed controls. In contrast, single-housed females maintained a similar body temperature to group-housed controls by increasing their metabolic rate. With decreasing ambient temperature below 27 °C, only group-housed mice decreased their heat conductance, likely due to huddling, thus interfering with the energy expenditure vs ambient temperature relationship described by Scholander. In a hot environment (35 °C), the single-housed mice were less heat stressed. Upon fasting, single-housed mice had larger reductions in body temperature, with male mice having more torpor episodes of similar duration and female mice having a similar number of torpor episodes that lasted longer. Qualitatively, the effects of housing density on thermal physiology of Brs3-null mice generally mimicked the effects in controls. Conclusions Single housing is more sensitive than group housing for detecting thermal physiology phenotypes. Single housing increases heat loss and amplifies the effects of fasting or a cold environment. Male and female mice utilize different thermoregulatory strategies to respond to single housing., Graphical abstract Image 1, Highlights • Changing housing density changes thermal physiology and metabolic rate. • Singly housed mice are more affected by fasting and by cold temperatures. • Single housing is more sensitive than group housing for detecting thermal phenotypes. • Certain principles of thermal physiology are masked by group housing. • Male and female mice respond differently to single housing.

Objective Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD+), an essential co-substrate regulating a myriad of signaling pathways. We produced a mouse that overexpressed NAMPT in skeletal muscle (NamptTg) and hypothesized that NamptTg mice would have increased oxidative capacity, endurance performance, and mitochondrial gene expression, and would be rescued from metabolic abnormalities that developed with high fat diet (HFD) feeding. Methods Insulin sensitivity (hyperinsulinemic-euglycemic clamp) was assessed in NamptTg and WT mice fed very high fat diet (VHFD, 60% by kcal) or chow diet (CD). The aerobic capacity (VO2max) and endurance performance of NamptTg and WT mice before and after 7 weeks of voluntary exercise training (running wheel in home cage) or sedentary conditions (no running wheel) were measured. Skeletal muscle mitochondrial gene expression was also measured in exercised and sedentary mice and in mice fed HFD (45% by kcal) or low fat diet (LFD, 10% by kcal). Results NAMPT enzyme activity in skeletal muscle was 7-fold higher in NamptTg mice versus WT mice. There was a concomitant 1.6-fold elevation of skeletal muscle NAD+. NamptTg mice fed VHFD were partially protected against body weight gain, but not against insulin resistance. Notably, voluntary exercise training elicited a 3-fold higher exercise endurance in NamptTg versus WT mice. Mitochondrial gene expression was higher in NamptTg mice compared to WT mice, especially when fed HFD. Mitochondrial gene expression was higher in exercised NamptTg mice than in sedentary WT mice. Conclusions Our studies have unveiled a fascinating interaction between elevated NAMPT activity in skeletal muscle and voluntary exercise that was manifest as a striking improvement in exercise endurance., Highlights • Skeletal muscle NAMPT overexpression increases NAD+ via elevated NAMPT activity. • Elevated NAMPT partially protects against very-high-fat-diet-induced weight gain. • Elevated NAMPT amplifies exercise-induced improvements in exercise endurance. • Fascinating interaction between elevated NAMPT activity in muscle and exercise.

Objective Obesity and high fat diet (HFD) consumption in rodents is associated with hypothalamic inflammation and reactive gliosis. While neuronal inflammation promotes HFD-induced metabolic dysfunction, the role of astrocyte activation in susceptibility to hypothalamic inflammation and diet-induced obesity (DIO) remains uncertain. Methods Metabolic phenotyping, immunohistochemical analyses, and biochemical analyses were performed on HFD-fed mice with a tamoxifen-inducible astrocyte-specific knockout of IKKβ (GfapCreERIkbkbfl/fl, IKKβ-AKO), an essential cofactor of NF-κB-mediated inflammation. Results IKKβ-AKO mice with tamoxifen-induced IKKβ deletion prior to HFD exposure showed equivalent HFD-induced weight gain and glucose intolerance as Ikbkbfl/fl littermate controls. In GfapCreERTdTomato marker mice treated using the same protocol, minimal Cre-mediated recombination was observed in the mediobasal hypothalamus (MBH). By contrast, mice pretreated with 6 weeks of HFD exposure prior to tamoxifen administration showed substantially increased recombination throughout the MBH. Remarkably, this treatment approach protected IKKβ-AKO mice from further weight gain through an immediate reduction of food intake and increase of energy expenditure. Astrocyte IKKβ deletion after HFD exposure—but not before—also reduced glucose intolerance and insulin resistance, likely as a consequence of lower adiposity. Finally, both hypothalamic inflammation and astrocytosis were reduced in HFD-fed IKKβ-AKO mice. Conclusions These data support a requirement for astrocytic inflammatory signaling in HFD-induced hyperphagia and DIO susceptibility that may provide a novel target for obesity therapeutics., Graphical abstract Overview of astrocyte IKKβ inactivation in chronic HFD-fed mice. Rodents exposed to HFD have increased hypothalamic inflammation and accumulation of reactive astrocytes in the mediobasal hypothalamus. Conditional deletion of IKKβ/NFκB in astrocytes of HFD-fed mice results in obesity resistance, improved glucose homeostasis, and decreased hypothalamic inflammation. 3V = third ventricle, Highlights • The first direct evidence that astrocyte inflammatory activation promotes obesity. • GfapCreER mice given tamoxifen show minimal recombination in MBH astrocytes. • GfapCreER mice given tamoxifen after 6 wks of HFD have recombination in the MBH. • Astrocyte IKKβ deletion with tamoxifen before HFD has no effect on energy balance. • Astrocyte IKKβ deletion with tamoxifen given after HFD reduces DIO susceptibility.

Objective Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. Method White and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. Results Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. Conclusions We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells., Highlights • Hig2 localizes to lipid droplets in adipocytes and promotes adipose tissue lipid deposition. • Its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. • Metabolic improvements are independent of changes in lipolysis.

Objective Non-alcoholic fatty liver disease is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mammalian homolog of INDY: mINDY). In Drosophila melanogaster and Caenorhabditis elegans INDY reduction decreased whole-body lipid accumulation. Genetic deletion of Slc13a5 in mice protected from diet-induced adiposity and insulin resistance. We hypothesized that inducible hepatic mINDY inhibition should prevent the development of fatty liver and hepatic insulin resistance. Methods Adult C57BL/6J mice were fed a Western diet (60% kcal from fat, 21% kcal from carbohydrate) ad libitum. Knockdown of mINDY was induced by weekly injection of a chemically modified, liver-selective siRNA for 8 weeks. Mice were metabolically characterized and the effect of mINDY suppression on glucose tolerance as well as insulin sensitivity was assessed with an ipGTT and a hyperinsulinemic-euglycemic clamp. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. Results Within the 8 week intervention, hepatic mINDY expression was suppressed by a liver-selective siRNA by over 60%. mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production) of C57BL/6J mice in the hyperinsulinemic-euglycemic clamp. Moreover, the siRNA-mediated mINDY inhibition prevented neutral lipid storage and triglyceride accumulation in the liver, while we found no effect on body weight. Conclusions We show that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice. These effects did not depend on changes of body weight or body composition., Graphical abstract, Highlights • mINDY/Slc13a5 knockdown was induced by liver-selective siRNA in mice. • Liver-selective knockdown of mINDY improved hepatic insulin sensitivity. • Liver-selective knockdown of mINDY prevented steatosis hepatis.

Background: Imbalances of the autonomic nervous (ANS), the cardiovascular system, and ionics might contribute to the manifestation of The Brugada Syndrome (BrS). Thus, this study has aimed to investigate the cardio-respiratory fitness and the responses of the ANS both at rest and during a sub-maximal exercise stress test, in BrS patients and in gender-matched and age-matched healthy sedentary controls. Methods: Eleven BrS patients and 23 healthy controls were recruited in Khon Kaen, Thailand. They performed an exercise test on a cycle ergometer, and during the exercise, expired gas samples and electrocardiograms were collected. Blood glucose and electrolyte concentrations were analyzed before and after exercise. Then the heart rate variability (HRV) and the heart rate recovery (HRR) were analyzed from the electrocardiograms. Results: The BrS patients showed a higher parasympathetic activation during exercise recovery than baseline. They had a smaller level of sympathetic activation during the period of exercise recovery than the controls did. They also showed a significantly lower peak HR, HRR, and peak oxygen consumption than the controls (p

Objective Obesity and type 2 diabetes (T2D) lead to various life-threatening diseases such as coronary heart disease, stroke, osteoarthritis, asthma, and neurodegeneration. Therefore, extensive research is ongoing to identify novel pathways that can be targeted in obesity/T2D. Deletion of the inositol pyrophosphate (5-IP7) biosynthetic enzyme, inositol hexakisphosphate kinase-1 (IP6K1), protects mice from high fat diet (HFD) induced obesity (DIO) and insulin resistance. Yet, whether this pathway is a valid pharmacologic target in obesity/T2D is not known. Here, we demonstrate that TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine], a pan-IP6K inhibitor, has strong anti-obesity and anti-diabetic effects in DIO mice. Methods Q-NMR, GTT, ITT, food intake, energy expenditure, QRT-PCR, ELISA, histology, and immunoblot studies were conducted in short (2.5-week)- and long (10-week)-term TNP treated DIO C57/BL6 WT and IP6K1-KO mice, under various diet and temperature conditions. Results TNP, when injected at the onset of HFD-feeding, decelerates initiation of DIO and insulin resistance. Moreover, TNP facilitates weight loss and restores metabolic parameters, when given to DIO mice. However, TNP does not reduce weight gain in HFD-fed IP6K1-KO mice. TNP specifically enhances insulin sensitivity in DIO mice via Akt activation. TNP decelerates weight gain primarily by enhancing thermogenic energy expenditure in the adipose tissue. Accordingly, TNP's effect on body weight is partly abolished whereas its impact on glucose homeostasis is preserved at thermoneutral temperature. Conclusion Pharmacologic inhibition of the inositol pyrophosphate pathway has strong therapeutic potential in obesity, T2D, and other metabolic diseases., Highlights • Pharmacologic inhibition of IP6K by TNP, at the onset of high fat feeding, decelerates initiation of DIO and insulin resistance in mice. • TNP, when treated to DIO mice, promotes weight loss and restores metabolic homeostasis. • TNP does not reduce high fat diet induced weight gain in IP6K1-KO mice. • TNP promotes insulin sensitivity by stimulating Akt activity, whereas it reduces body weight primarily by enhancing thermogenic energy expenditure. • Long-term TNP treatment does not display deleterious side effects.

Objective The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. Methods To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5−/−). Results Ablation of ACSL5 reduced ACSL activity by ∼80% in jejunal mucosa, ∼50% in liver, and ∼37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5−/−, as compared to control ACSL5loxP/loxP, mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5−/− had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5−/− mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (∼16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (∼13-fold) were increased in ACSL5−/− as compared to ACSL5loxP/loxP. Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5−/− mice as compared to control mice. Conclusions In summary, ACSL5−/− mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance., Graphical abstract, Highlights • Role of acyl CoA synthetase 5 (ACSL5) in systemic metabolism was studied in an ACSL5 deficient mouse. • ACSL5 deficiency reduced total ACSL activity in liver, intestine, and brown adipose tissue. • ACSL5 deficient mice had increased hepatic and circulating FGF21 expression and energy expenditure. • ACSL5 deficient mice demonstrated delayed triglyceride absorption.

TGR5, a G protein-coupled bile acid receptor, is expressed in various tissues and regulates several physiological processes. In the skeletal muscle, TGR5 activation is known to induce muscle hypertrophy; however, the effects on glucose and lipid metabolism are not well understood, despite the fact that the skeletal muscle plays a major role in energy metabolism. Here, we demonstrate that skeletal muscle-specific TGR5 transgenic (Tg) mice exhibit increased glucose utilization, without altering the expression of major genes related to glucose and lipid metabolism. Metabolite profiling analysis by capillary electrophoresis time-of-flight mass spectrometry showed that glycolytic flux was activated in the skeletal muscle of Tg mice, leading to an increase in glucose utilization. Upon long-term, high-fat diet challenge, blood glucose clearance was improved in Tg mice without an accompanying increase in insulin sensitivity in skeletal muscle and a reduction of body weight. Moreover, Tg mice showed improved age-associated glucose intolerance. These results strongly suggest that TGR5 ameliorated glucose metabolism disorder that is caused by diet-induced obesity and aging by enhancing the glucose metabolic capacity of the skeletal muscle. Our study demonstrates that TGR5 activation in the skeletal muscle is effective in improving glucose metabolism and may be beneficial in developing a novel strategy for the prevention or treatment of hyperglycemia.

Objective: Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction. Methods: Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj−/− (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake. Results: High-fat diet fed-Ptprj−/− mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj−/− mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj−/− mice. Conclusion: Together, these data establish DEP-1 as novel negative regulator of insulin signaling.

Objective: Type 2 diabetes arises from insulin resistance of peripheral tissues followed by dysfunction of β-cells in the pancreas due to metabolic stress. Both depletion and supplementation of neutral amino acids have been discussed as strategies to improve insulin sensitivity. Here we characterise mice lacking the intestinal and renal neutral amino acid transporter B0AT1 (Slc6a19) as a model to study the consequences of selective depletion of neutral amino acids. Methods: Metabolic tests, analysis of metabolite levels and signalling pathways were used to characterise mice lacking the intestinal and renal neutral amino acid transporter B0AT1 (Slc6a19). Results: Reduced uptake of neutral amino acids in the intestine and loss of neutral amino acids in the urine causes an overload of amino acids in the lumen of the intestine and reduced systemic amino acid availability. As a result, higher levels of glucagon-like peptide 1 (GLP-1) are produced by the intestine after a meal, while the liver releases the starvation hormone fibroblast growth factor 21 (FGF21). The combination of these hormones generates a metabolic phenotype that is characterised by efficient removal of glucose, particularly by the heart, reduced adipose tissue mass, browning of subcutaneous white adipose tissue, enhanced production of ketone bodies and reduced hepatic glucose output. Conclusions: Reduced neutral amino acid availability improves glycaemic control. The epithelial neutral amino acid transporter B0AT1 could be a suitable target to treat type 2 diabetes.

Background/objectives Fasting dyslipidemia is commonly observed in insulin resistant states and mechanistically linked to hepatic overproduction of very low density lipoprotein (VLDL). Recently, the incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in ameliorating dyslipidemia associated with insulin resistance and reducing hepatic lipid stores. Given that hepatic VLDL production is a key determinant of circulating lipid levels, we investigated the role of both peripheral and central GLP-1 receptor (GLP-1R) agonism in regulation of VLDL production. Methods The fructose-fed Syrian golden hamster was employed as a model of diet-induced insulin resistance and VLDL overproduction. Hamsters were treated with the GLP-1R agonist exendin-4 by intraperitoneal (ip) injection for peripheral studies or by intracerebroventricular (ICV) administration into the 3rd ventricle for central studies. Peripheral studies were repeated in vagotomised hamsters. Results Short term (7–10 day) peripheral exendin-4 enhanced satiety and also prevented fructose-induced fasting dyslipidemia and hyperinsulinemia. These changes were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma. The observed changes in fasting dyslipidemia could be partially explained by reduced respiratory exchange ratio (RER) thereby indicating a switch in energy utilization from carbohydrate to lipid. Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation. Despite these observations, GLP-1R activity could not be detected in primary hamster hepatocytes, thus leading to the investigation of a potential brain–liver axis functioning to regulate lipid metabolism. Short term (4 day) central administration of exendin-4 decreased body weight and food consumption and further prevented fructose-induced hypertriglyceridemia. Additionally, the peripheral lipid-lowering effects of exendin-4 were negated in vagotomised hamsters implicating the involvement of parasympathetic signaling. Conclusion Exendin-4 prevents fructose-induced dyslipidemia and hepatic VLDL overproduction in insulin resistance through an indirect mechanism involving altered energy utilization, decreased hepatic lipid synthesis and also requires an intact parasympathetic signaling pathway.