Palmitoleic acid reduces intramuscular lipid and restores insulin sensitivity in obese sheep

Susan K Duckett, Gabriela Volpi-Lagreca, Mariano Alende, Nathan M Long, Susan K Duckett, Gabriela Volpi-Lagreca, Mariano Alende, Nathan M Long

Abstract

Obese sheep were used to assess the effects of palmitoleic (C16:1 cis-9) acid infusion on lipogenesis and circulating insulin levels. Infusion of 10 mg/kg body weight (BW)/day C16:1 intravenously in obese sheep reduced (P<0.01) weight gain by 77%. Serum palmitoleic levels increased (P<0.05) in a linear manner with increasing levels of C16:1 infusion. Cis-11 vaccenic (C18:1 cis-11) acid, a known elongation product of palmitoleic acid, was also elevated (P<0.05) in serum after 14 days and 21 days of infusion. Plasma insulin levels were lower (P<0.05) (10 mg/kg BW/day C16:1) than controls (0 mg/kg BW/day C16:1) at 14 days and 28 days of infusion. Infusion of C16:1 resulted in linear increases in tissue concentrations of palmitoleic, cis-11 vaccenic, eicosapentaenoic, and docosapentaenoic acids in a dose-dependent manner. Total lipid content of the semitendinosus (ST) muscle and mesenteric adipose tissue was reduced (P<0.01) in both 5 mg/kg and 10 mg/kg BW C16:1 dose levels. Total lipid content and mean adipocyte size in the longissimus muscle was reduced (P<0.05) in the 10 mg/kg BW C16:1 dose level only, whereas total lipid content and adipocyte size of the subcutaneous adipose tissue was not altered. Total lipid content of the liver was also unchanged with C16:1 infusion. Palmitoleic acid infusion upregulated (P<0.05) acetyl-CoA carboxylase (ACC), fatty acid elongase-6 (ELOVL6), and Protein kinase, AMP-activated, alpha 1 catalytic subunit, transcript variant 1 (AMPK) mRNA expressions in liver, subcutaneous adipose, and ST muscle compared to the controls. However, mRNA expression of glucose transporter type 4 (GLUT4) and carnitine palmitoyltransferase 1b (CPT1B) differed between tissues. In the subcutaneous adipose and liver, C16:1 infusion upregulated (P<0.05) GLUT4 and CPT1B, whereas these genes were downregulated (P<0.05) in ST muscle with C16:1 infusion. These results show that C16:1 infusion for 28 days reduced weight gain, intramuscular adipocyte size and total lipid content, and circulating insulin levels. These changes appear to be mediated through alterations in expression of genes regulating glucose uptake and fatty acid oxidation specifically in the muscles.

Keywords: adipocytes; fatty acid; insulin level; lipogenesis; longissimus muscle; serum.

Figures

Figure 1
Figure 1
Effects of palmitoleic acid infusion on serum cis-11 vaccenic acid levels. Notes: Changes in serum cis-11 vaccenic (C18:1 cis-11) acid concentration (μg/mL) by palmitoleic acid infusion level (0 mg/kg LW/d, 5 mg/kg LW/d, or 10 mg/kg LW/d) at 5 minutes post-dosing by time of the experiment. Abbreviations: LW, lipid weight; d, days.
Figure 2
Figure 2
Changes in plasma insulin concentration and HOMA-IR values with palmitoleic acid infusion at three levels. Notes: Plasma insulin concentrations (μIU/mL) (A) and HOMA-IR (B) in lambs infused with varying levels of palmitoleic (C16:1) acid levels (0 mg/kg LW/d, 5 mg/kg LW/d, or 10 mg/kg LW/d) by day of experiment. Abbreviations: LW, lipid weight; d, days; HOMA-IR, Homeostatis Model Assessment-Insulin Resistance.
Figure 3
Figure 3
Effects of palmitoleic acid infusion on intramuscular lipid content. Notes: Total lipid content (g/100 g of tissue) of liver, LM, and ST muscle (A), and SQ and MS fat (B) in lambs infused with varying levels of palmitoleic (C16:1) acid levels (0 mg/kg LW/d, 5 mg/kg LW/d, or 10 mg/kg LW/d) for 28 d. Abbreviations: LM, longissimus muscle; ST, semitendinosus; SQ, subcutaneous; MS, mesenteric; LW, lipid weight; d, days.
Figure 4
Figure 4
Effects of palmitoleic acid infusion on mean adipocyte size and distribution. Notes: Mean adipocyte size (μm) (A) for both IM and SQ adipose tissues, and adipocyte size distribution (μm) (B) for IM adipose tissues by palmitoleic acid infusion level. IM adipocyte size was smaller (P<0.05) in palmitoleic acid infusion for dose level 10 mg/kg BW/d. Abbreviations: LW, lipid weight; d, days; IM, intramuscular; SQ, subcutaneous; BW, body weight.
Figure 5
Figure 5
Fold-change in lipogenic gene expression for 10 mg C16:1/kg LW/d versus control (0 mg/kg BW/d) averaged over the three tissues (subcutaneous adipose tissue, ST muscle, and liver). Notes: *P<0.05. **P<0.01. Abbreviations: BW, body weight; LW, lipid weight; d, days; ST, semitendinosus; SCD, stearoyl-CoA desaturase; FASN, fatty acid synthase; ACC, acetyl-CoA carboxylase; ELOVL5, fatty acid elongase-5; ELOVL6, fatty acid elongase-6; CPT1a, carnitine palmitoyltransferase 1a; HSL, hormone-sensitive lipase; FABP4, fatty acid binding protein 4.
Figure 6
Figure 6
Effects of palmitoleic acid infusion on gene expression and protein content of tissues. Notes: Fold-change in glucose/insulin-related gene expression (A) for 10 mg C16:1/kg LW/d versus control (0 mg/kg BW/d) averaged over the three tissues (subcutaneous adipose tissues, ST muscle, and liver). Density of AMPKα1 protein density (B), pAMPKα1 protein density (C), and ratio of pAMPKα1 to AMPKα1 for 10 mg C16:1/kg LW/d versus control (0 mg/kg BW/d) averaged over the three tissues (subcutaneous adipose tissues, ST muscle, and liver). *P<0.05. Abbreviations: LW, lipid weight; d, days; BW, body weight; ST, semitendinosus; AMPK, protein kinase, AMP-activated, alpha 1 catalytic subunit, transcript variant 1; P13KR1, phosphoinositide-3-kinase, regulatory subunit 1 (alpha); IR, insulin receptor; AKT1,v-akt murine thymoma viral oncogene homolog 1; IRS1, insulin receptor substrate 1.
Figure 7
Figure 7
Palmitoleic acid infusion alters gene expression differentially by tissue. Notes: Fold-change in gene expression for 10 mg C16:1/kg LW/d versus control (mg/kg LW/d) by tissue (subcutaneous adipose, liver, and ST muscle). The interaction between palmitoleic acid infusion and tissue (ST, SQ, liver) was significant (P<0.05) for GLUT4 and CPT1b. *P<0.05. **P<0.01. Abbreviations: LW, lipid weight; d, days; ST, semitendinosus; SQ, subcutaneous; GLUT4, glucose transporter type 4; CPT1b, carnitine palmitoyltransferase 1b.

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