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Published in final edited form as: Peptides. 2009 Oct 31;31(1):123–129. doi: 10.1016/j.peptides.2009.10.018

The metabolic phenotype of SCD1-deficient mice is independent of melanin-concentrating hormone

Melissa B Glier a,*, Pavlos Pissios b, Sandra L Babich a, Marcia LE Macdonald c, Michael R Hayden c, Eleftheria Maratos-Flier b, William T Gibson a
PMCID: PMC4096855  NIHMSID: NIHMS602233  PMID: 19883709

Abstract

We propose that deletion of pro-melanin-concentrating hormone (pMCH) would increase energy expenditure and further improve glucose tolerance in mice lacking stearoyl-coA desaturase-1 (SCD1). To test our hypothesis, we bred and metabolically challenged Pmch−/−; Scd1−/− double-knockout mice, with comparison to Pmch−/− mice; Scd1−/− mice and C57Bl/6J controls. Deletion of both Pmch and Scd1 increased both food intake and energy expenditure relative to control mice. Pmch−/−; Scd1−/− double-knockout mice had improved glucose tolerance relative to control mice. The majority of the metabolic effects were contributed by inactivation of the Scd1 gene. Weconclude that the increased food intake and increased energy expenditure of Scd1−/− mice are independent of the neuropeptide melanin-concentrating hormone.

Keywords: Stearoyl-CoA desturase-1, Energy metabolism, Melanin-concentrating hormone, Indirect calorimetry

1. Introduction

Leptin is an adipocyte-derived hormone that regulates energy intake, energy expenditure and substrate metabolism [23,25]. When circulating leptin levels decrease, the body acts to replenish energy stores by increasing food intake and decreasing energy expenditure. Leptin therapy reverses obesity in leptin-deficient mice and humans [5,7,14], but variable effects were seen among humans with common obesity [11]. Clinical interest in the leptin–melanocortin pathway remains high, and molecules downstream of leptin signaling have become attractive candidates for drug development. Two molecules targeted by the leptin-responsive pathway are SCD-1 and pMCH.

Stearoyl-CoA desaturase-1 (SCD-1) is a key lipogenic enzyme involved in the biosynthesis of monounsaturated fatty acids [13]. Scd1 is required for the full obese phenotype of ob/ob mice to manifest, and Scd1−/− mice exhibit increased energy expenditure and hyperphagia [2]. Mice deficient in Scd1 have decreased fat mass [2,13], reduced serum leptin levels [1] and improved insulin sensitivity [6]. Scd1 is overexpressed in the livers of hyperphagic ob/ob mice, and Scd1-deficient ob/ob mice are even more hyperphagic than are ob/ob control mice [3,13]. Scd1−/−; ob/ob mice also show increased lean mass, and a dramatic decrease in fat mass [3,13]. In fact, ablation of Scd1 reduces obesity of ob/ob mice to a degree comparable with leptin replacement [2]. Removal of Scd1 from ob/ob mice also normalizes hepatic lipid storage, a finding that proves liver Scd1 is a target of leptin signaling [1]. However, Scd1−/−; ob/ob mice have impaired insulin sensitivity relative to ob/ob mice, suggesting an uncoupling of the effects of SCD1 deficiency on body weight from those on glucose disposal in the Scd1−/−; ob/ob model [12].

Prepro-melanin-concentrating hormone (pMCH) is a hypothalamic neuropeptide that, like Scd1, plays a crucial role in energy homeostasis [10]. The arcuate nucleus of the hypothalamus is a major center for coordination of the central nervous system (CNS) response to leptin [19]. Orexigenic neurons in the lateral hypothalamus that express pMCH project widely throughout the cortex [18]. Mice deficient in Pmch have hypophagia and/or increased energy expenditure, depending on the genetic background [10,21]. Investigation of the relationship between Pmch and leptin using double-knockout mice found that Pmch deficient ob/ob mice have attenuated weight gain (vs. ob/ob mice on a chow diet), but remain hyperphagic [20]. Pmch−/−; ob/ob mice also have decreased fat mass and increased lean mass when compared with ob/ob mice [20]. Pmch deficient and Pmch−/−; ob/ob mice are lean secondary to increased energy expenditure, a fact which confirms the role for Pmch downstream of leptin [20]. ob/ob mice overexpress Pmch in the hypothalamus [18] and also overexpress Scd1 in the liver [2]. Furthermore, genetic ablation of Pmch attenuates Scd1 overexpression in ob/ob mice [20]. We hypothesized that Pmch is a key link between leptin and Scd1. We further hypothesized that genetic removal of Pmch and Scd1 in vivo should improve the body’s metabolic profile over and above the improvements seen with knockout of the individual molecules. We therefore set out to examine energy balance phenotypes in Pmch−/−; Scd1−/− mice.

2. Materials and methods

2.1. Mice and diets

Mice carrying the Scd1ab-2J null allele [22] were backcrossed to C57BL/6J for 10 generations and then crossed to mice lacking the gene for prepro-MCH [21] to create double-heterozygous Pmch+/−; Scd1+/− mice. Double-heterozygotes were bred with each other, and the Pmch−/−; Scd1+/− offspring were intercrossed to produce Pmch−/−; Scd1−/− double-knockout (dKO) mice. Pmch+/−; Scd1−/− parents also produced Pmch+/+; Scd1−/− (Scd1−/− or sKO) mice. Pmch+/−; Scd1+/+ mice were also interbred to produce Pmch−/−; Scd1+/+ (Pmch−/− or pKO) mice and Pmch+/+; Scd1+/+ (wild-type or WT) controls. Female mice were used for the following experiments. Animals were housed at the Child and Family Research Institute under an alternating 12:12-h light–dark cycle. Animals received a standard chow (LabDiet 5010 Autoclavable Rodent Diet: PMI Nutrition International, Richmond, IN). All experimental procedures were approved by the University of British Columbia’s Animal Care Committee.

2.2. Genotyping

Genotypes were confirmed by PCR amplification of mouse tail genomic DNA. In Pmch−/− mice, primers targeting the PGK-neo cassette [21] were used for PCR. The primers were: for Pmch 5′-GAATTTGGAAGATGACATAGTAT-3′ (sense) and 5′-CAGCCCGGTGAGTTACAAGATTCT-3′ (antisense); for PGK-neo, 5′-CGGGTAGGGGAGGCGCT-3′ (sense) and 5′-GCGCAAGGAACGCCCGTCGTG-3′ (antisense) [20,21]; for the Scd1 5-ATCATACTGGTTCCCTCCTGCAAGC-3′ (sense) and 5′-GAGCAAAGAGAAATCTGAGGCACTGG-3′ (antisense).

2.3. Body weight and body composition measurements

Between 10 and 14 weeks of age, body weight was measured using a Denver Instrument XP-300 scale (Denver, CO). Body composition (fat and lean mass) was measured using quantitative magnetic resonance (QMR) (EchoMRI, Houston, TX).

2.4. Energy balance physiology measurements

Between 10 and 14weeks of age, energy balance and home-cage activity were recorded using a combined indirect calorimetry system (LabMaster Cages, TSE-Systems, Bad Homburg, Germany). After 24–48 h of initial acclimatization, food intake, water intake, energy expenditure, resting energy expenditure, and respiratory exchange ratio were measured every 15min for a total of 58 h. Resting energy expenditure was calculated by taking the average of the five lowest values of energy expenditure [4]. Along with total locomotor activity, stationary, ambulatory and rearing movements were recorded in the X, Y, andZ axes using infrared light beams [15].

2.5. Glucose tolerance test

Mice 4–6 months of age were fasted for 5 h. Glucose (2 g/kg of body weight) was administered through an intraperitoneal injection. Lateral saphenous blood was collected at 0, 15, 30, 60, 90 and 120 min. Blood glucose was measured using a glucometer (Breeze 2, Toronto, ONT).

2.6. Insulin tolerance test

Mice at 4–6 months of age were fasted for 5 h. Human insulin (Novo Nordisk, Mississauga, ONT) at a dose of 0.75 U/μ was administered through an intraperitoneal injection. Lateral saphenous blood was collected at 0, 15, 30, 60, 90 and 120 min.

2.7. Hormonal measurements

Mice 4–6 months of age were fasted for 5 h. Approximately 200 μL of whole blood was collected via lateral saphenous vein into EDTA-coated Sarstedt, and non-coated Sarstedt, Microvette tube. Plasma insulin levels were measured using Enzyme Immuno Assay (EIA – Alpco Diagnostics, Salem, NH; Cat. No. 80-INSMSU-E01). Serum leptin levels were measured using Enzyme Immuno Assay (EIA – Alpco Diagnostics, Salem, NH; Cat. No. 22-LEPMS-EO1).

2.8. Statistical analysis

Means ± SE are shown. Differences between the groups were calculated by one-way ANOVA or with repeated-measures ANOVA and with Bonferroni or Dunnett’s post-tests.

3. Results

3.1. Body mass measurements

pKO mice weighed less than other strains, an effect which reached significance for sKO and dKO mice (Table 1, ANOVA P = 0.0001). aKO and dKO weighed more than dWT mice (Table 1, P < 0.001). pKO mice also had lower fat mass than any other strain (Table 1, ANOVA P < 0.0025). Lean mass was not different between pKO mice and controls, but both sKO and dKO mice had increased lean mass relative to pKO and dWT(B6) mice (Table 1, ANOVA P < 0.0001).

Table 1.

Physical and metabolic characteristics (mean±SEM).

dWT pKO sKO dKO
Total body weight, g 18.6±0.5 (n = 12) 18.6±0.4 (n=8) 22.4±0.8 (n=5) 21.1±0.4 (n=9)
Fat mass, g 2.6±0.2 (n = 12) 1.8±0.1 (n=8) 2.6±0.1 (n=5) 2.4±0.1 (n=9)
Lean mass, g 14.8±0.4 (n = 12) 15.0±0.3 (n=8) 18.1±0.2 (n=5) 18.0±0.4 (n=9)
Baseline glucose, mmol/L 9.8±0.4 (n = 15) 9.4±0.8 (n=6) 10.0±0.7 (n=8) 8.5±0.4 (n=9)
Insulin, ng/mL 0.50±0.20 (n = 14) 0.10±0.03 (n=3) 0.40±0.09 (n=7) 0.30±0.04 (n = 11)
Leptin, ng/mL 0.4±0.3 (n=4) 0.3±0.1 (n=3) 0.4±0.2 (n=2) 0.3±0.1 (n=8)
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3.2. Hormone homeostasis

We found no differences in fasting glucose or insulin levels among the genotypes (Table 1); though plasma glucose in dKO mice was somewhat lower, the difference did not reach statistical significance. We did find improved glucose tolerance in all three knockout strains relative to dWT controls (Fig. 1A – repeated-measures ANOVA P < 0.0001, in agreement with AUC analysis Fig. 1B), though there were no significant differences in glucose tolerance between pKO, sKO and dKO mice. Insulin tolerance test in dKO and control mice found no difference between the strains (Fig. 1C and D). Fasting leptin levels did not differ among genotypes (Table 1).

Fig. 1.

Fig. 1

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Glucose homeostasis and plasma insulin levels. Using an intraperitoneal dose of 2 g/kg of body weight, a glucose tolerance test in 6 dWT, 6 pKO, 3 sKO, and 9 dKO mice (A), showed that dKO mice have improved glucose tolerance compared with dWT controls during the 120-min study period. Area under the curve values confirmed the results found in the glucose tolerance (B). Using an intraperitoneal dose of 0.75 U/μ of body weight, an insulin tolerance test in 7 dWT, and 5 dKO mice (C) showed no differences between the strains, results confirmed by area under the curve analysis (D). Values are means ± SEM. *P < 0.05 vs. WT.

3.3. Food intake

dKO and sKO mice show increased food intake during the light phases (Fig. 2A, ANOVA P < 0.0353) and during the dark phases (Fig. 2A, shaded, ANOVA P < 0.0001). This phenotype persisted when intake was normalized to body weight (Fig. 2A, left, middle, P < 0.0001) and lean mass (Fig. 2A, left, bottom, P < 0.0005).

Fig. 2.

Fig. 2

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Food intake. Ingestive behavior was calculated in 12 dWT, 8 pKO, 5 sKO, and 9 dKO mice given ad libitum access to standard chow diet. During a representative 58-h observation period (A, right) cumulative food intake during the dark phase (A, left, top) was increased in dKO mice, compared with dWT mice. This difference persisted when consumption was normalized to body weight (A, left, middle), and lean mass (A, left, bottom). Values are means ± SEM. *P < 0.05 vs. WT, and #P < 0.05 vs. pKO.

3.4. Energy expenditure

dKO and sKO mice also show increased energy expenditure on a per mouse basis (data not shown) when compared with dWT control mice during the light (P < 0.0001) and dark phases (P < 0.0001). The effect of genotype on energy expenditure remains when normalized to body weight and when normalized to metabolically active lean tissue during the light and dark phases (Fig. 3A, all post hoc P < 0.0001). We observed a normal diurnal fluctuation in food intake (Fig. 3A, left panels), and energy expenditure (Fig. 3A, right panels). Resting energy expenditure is increased in dKO mice when compared with dWT and pKO (Fig. 3B, left, P < 0.0001) mice. Resting energy expenditure also remains increased in these mice when normalized to metabolically active lean tissue (Fig. 3B, right, P < 0.0001). There was no significant difference in REE in dKO mice compared to sKO mice.

Fig. 3.

Fig. 3

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Energy expenditure, and resting energy expenditure. The average energy expenditure (A) and the basal metabolic rate (B) were measured in 12 dWT, 8 pKO, 5 sKO, and 9 dKO mice for a period of 58 h. dKO mice showed a significantly higher energy expenditure than dWT mice in both the dark and light phase (A, left, top). Normalization to metabolically active lean tissue persisted after the increase in energy expenditure (A, left, bottom). Basal metabolic rate was higher in dKO mice compared with dWT mice. Values are means ± SEM. *P < 0.05 vs. WT, and #P < 0.05 vs. pKO.

3.5. Physical activity

pKO mice show increased TLA relative to controls during the dark phase (Fig. 5, left, ANOVA P = 0.0048) but not during the light phase. We observed a normal diurnal fluctuation in total locomotor activity (Fig. 5, right).

Fig. 5.

Fig. 5

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Total locomotor activity. The total locomotor activity was measured in 12 dWT, 8 pKO, 5 aKO, and 9 dKO mice for a period of 58 h. pKO mice show a significantly increased total locomotor activity during the dark phases than other genotypes. Values are means ± SEM. *P < 0.05 vs. WT, and #P < 0.05 vs. pKO.

3.6. Respiratory exchange ratio

The dKO mice show a significantly lower RER during the light phase than did controls (P = 0.0291, Fig. 4, left). The circadian–ultradian periodicity was preserved (Fig. 4, right).

Fig. 4.

Fig. 4

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Respiratory exchange ratio. The average respiratory exchange ratio was measured in 12 dWT, 8 pKO, 5 sKO, and 9 dKO mice for a period of 58 h. dKO mice showed a significantly lower respiratory exchange ratio than dWT mice in the light phase (A, left). Values are means ± SEM. *P < 0.05 vs. WT.

4. Discussion

Leptin-deficient ob/ob mice overexpress Pmch in hypothalamus [18] and Scd1 in liver [2], and genetic ablation of Pmch attenuates liver Scd1 overexpression [20]. These previous findings suggested us that coordinate regulation of these two molecules by leptin might have physiological relevance. Information on energy balance in multiple tissues and organs is presented to the brain via humoral (endocrine) and neuronal afferent signals. When energy storage is excessive, the brain sends out efferent signals to enhance energy expenditure and lipolysis. In the rat brain, dense projections of MCH-immunoreactive axons from the dorsomedial and lateral hypothalamus arrive at the dorsal motor nucleus of the vagus, the nucleus tractus solitarius, and sympathetic premotor areas of the ventral medulla [26,9]. These caudal projections of MCH neurons to brainstem sites could plausibly regulate autonomic responses [16]. The liver is known to transmit autonomic signals to the brain via the afferent loop of the hepatic vagus nerve, which in turn modulates insulin sensitivity and energy expenditure [24]. It is possible that the efferent arm of the vagus receives input from the aforementioned MCH-ergic projections, and that this anatomical connection from the brainstem to the liver modulates hepatic Scd1 activity.

We sought to investigate metabolic links between melanin-concentrating hormone and stearoyl coA desaturase. Since deletion of either melanin-concentrating hormone [21] or stearoyl coA desaturase [2,13] increases energy expenditure, we hypothesized that deletion of both genes would increase energy expenditure more significantly, and improve the metabolic phenotype of the B6 mouse strain. Removal of Pmch from an ob/ob background did not affect the food intake of hyperphagic ob/ob mice [20], so we hypothesized that deletion of Pmch from the hyperphagic Scd1−/− background would leave food intake unchanged, and exert effects on energy balance primarily through effects on energy expenditure. Consistent with others, we observed an increased in TLA Pmch−/− mice relative to controls along with the increased energy expenditure observed by others [8]. We observed a significant increase in both resting and total energy expenditure in double-knockout mice relative to wild-type mice. The absence of SCD1 activity appeared to be the major quantitative contributor to the double-knockout phenotype, with a minor contribution from removal of Pmch. Consistent with earlier reports; deletion of the Pmch gene did not affect the food intake of B6 mice. Consistent with our hypothesis, the food intake of Scd1-deficient mice was not affected by deletion of the Pmch gene. This provides further weight to existing evidence that Pmch and its products exert their physiological effects primarily on the energy expenditure arm of the energy homeostasis equation.

Removal of Pmch from B6 mice had specific effects on fat mass, without affecting lean mass. Our QMR system does not measure bone mass, so the possibility that these mice also had some degree of reduction in bone mass remains unexplored. It is interesting to note that removal of Pmch from Scd1−/− mice did not reduce fat mass. This suggests that the excess food intake that results from SCD1 deficiency outweighs the reduction in fat mass that would otherwise be associated with Pmch deficiency, even in the context of increased energy expenditure. Both sKO and dKO mice show reductions in RER during light phase dormancy, reflecting a relative shift away from carbohydrate and toward fat for energy requirements. Thus, the fact that fat mass does not differ between dWT, sKO and dKO genotypes cannot be explained through changes in macronutrient mobilization for energy needs. The quantitative effect of the reduced RER seen in the Scd1−/− and Pmch−/−; Scd1−/− mice would be expected to reduce fat mass rather than increase it. We conclude that the hyperphagia caused by Scd1 deficiency is quantitatively sufficient to increase fat mass despite the increase in energy expenditure mediated by deficiency of both molecules. Though deletion of the Pmch gene from Scd1−/− mice may subtly increase the total and resting energy expenditure, result for REE only reached statistical significance relative to Scd1−/− mice if a one-tailed post hoc t-test was used. The use of a one-tailed test was based on the prior evidence that removal of pMCH would only be expected to increase REE, not decrease it [10]. Nevertheless, a major effect of Pmch deficiency on the phenotype of the double-knockout mice was not detectable.

We did observe improvements in glucose tolerance in the dKO mice, but there did not appear to be any synergy of the individual gene knockouts on the phenotype, when compared to either of the parental genotypes. Further experimentation would be required to elucidate any such effects, perhaps via exposure of the mice to a high-fat and/or high-fat, high carbohydrate diet. We observed a small decrease in fasting insulin levels in Pmch−/− mice, one that did not reach statistical significance when compared with wild-type mice. Since Pmch is a known trophic factor for islet beta cells, this is not surprising [17]. The fact that glucose tolerance was improved in all three single knockout strains relative to wild-type, attests to the utility of increasing energy expenditure as a protective factor against glucose intolerance, even in the context of a presumptive decrease in beta cell function.

The interplay between neuropeptides that regulate energy homeostasis and end-organs that process energy-containing nutrients is of interest from a clinical perspective. Insights into these processes may eventually lead to new treatments for excessive liver fat, as occurs in obesity and lipodystrophy syndromes. Though our data do not directly address whether elevated levels of MCH might increase liver Scd1 activity via autonomic or other pathways, they do show that the increased energy expenditure of Scd1-deficient mice is mediated largely by non-MCH-ergic pathways.

Acknowledgments

This work was funded by CIHR INMD Operating Grant OOP-79614, with additional support from the Michael Smith Foundation for Health Research Childhood Diabetes Research Unit. Dr. Gibson was supported by a CIHR-IG Clinical Investigatorship, and is currently supported by Clinician Scientist Awards from CIHR and CFRI. We gratefully acknowledge Galina Soukhatcheva, Whitney Quong and Tiffany Ngai for technical assistance.

Abbreviations

dKO

mice homozygous for inactivating alleles of both the Pmch and Scd1 genes (Pmch−/−, Scd1−/− genotype)

dWT

mice homozygous for normal alleles of both the Pmch and Scd1 genes (Pmch+/+, Scd1+/+ genotype) (=B6)

pKO

“Pmch knockout” mice, with a homogygous engineered deletion of the Pmch gene (Pmch−/− genotype); pMCH, mouse pro-melanin-concentrating hormone protein

Pmch

mouse pro-melanin-concentrating hormone gene; SCD1, mouse stearoyl-CoA desturase-1 protein

Scd1

mouse stearoyl-CoA desturase-1 gene

B6

C57Bl/6J “wild-type” laboratory mice (=dWT); sKO, mice bearing homozygous Scd1ab-2J null alleles (Scd1−/− genotype).

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