An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption

Iqbal, Jahangir; Li, Xiaosong; Chang, Benny; Schwartz, Gary J.; Chua, Streamson C.; Hussain, M. Mahmood

doi:10.1194/jlr.m005744

Cited by 55 publications

(45 citation statements)

References 79 publications

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“…Likewise, icv infusion of the MC4R synthetic antagonist HS104 also failed to increase plasma TG levels in pair-fed rats ( 31 ). It should be noted that MC4R-defi cient mice have only modestly increased plasma TG levels compared with control mice (+30%) ( 32 ), implying that partial inhibition of MC4R by SHU9119 may be insuffi cient to signifi cantly increase plasma TG levels. In heterozygous MC4R-defi cient subjects, plasma TG levels are increased (1.7 vs. 1.3 mM) ( 33 ), indicating that the melanocortin system does play a role in the regulation of plasma VLDL-TG levels in humans.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the central melanocortin system decreases brown adipose tissue activity

Kooijman

Boon

Parlevliet

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words energy expenditure • liver • triglycerides • very low density lipoprotein • white adipose tissueThe hypothalamus is important in the regulation of energy balance. Activation of pro-opiomelanocortin neurons (e.g., by insulin or leptin) induces secretion of ␣ -melanocytestimulating hormone, which in turn stimulates melanocortin 3/4 receptors (MC3/4Rs) within the paraventricular nucleus to cause a negative energy balance ( 1 ). Accordingly, activation of central melanocortin 4 receptor (MC4R) in rodent models results in anorexia and weight loss ( 2 ), whereas blockade or targeted gene disruption induces hyperphagia and obesity, even on regular chow diet ( 3, 4 ). Loss-of-function mutations in MC4R are the most common monogenic form of obesity in humans and are associated with severe obesity in childhood ( 5 ). In addition, recent meta-analyses of genome-wide association studies identifi ed common variants near MC4R to infl uence fat mass, obesity, and obesity risk ( 6, 7 ). These observations support an essential role for the melanocortin system in the regulation of energy homeostasis across mammalian species.In addition to the effects of the melanocortin system on food intake, this system also affects energy balance via other pathways. This notion is supported by the observation that pharmacological inhibition of central MC4R by Abstract The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) defi ciency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet for 4 weeks and infused intracerebroventricularly with the melanocortin 3/4 receptor (MC3/4R) antagonist SHU9119 or vehicle for 2 weeks. SHU9119 increased food intake (+30%) and body fat (+50%) and decreased EE by reduction in fat oxidation ( ؊ 42%). In addition, SHU9119 impaired the uptake of VLDL-TG by BAT. In line with this, SHU9119 decreased uncoupling protein-1 levels in BAT ( ؊ 60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Finally, SHU9119-treated mice pair-fed to the vehicletreated group still exhibited these effects, indicating that MC4R inhibition impairs BAT activity independent of food intake. These effects were not specifi c to the APOE*3-Leiden.CETP background as SHU9119 also inhibited BAT activity in wild-type mice. We conclude that inhibition of central MC3/4R signaling impairs BAT function, which is accompanied by reduced EE, thereby promoting adiposity. We anticipate that activation of MC4R is a promising strategy to combat obesity by increasing BAT activity. -Kooijman, S., M. R. Boon, E. T. Parlevliet, J. J. Geerling, V. van de Pol, J. A. Romijn, L. M. Havekes, I. Meurs, and P. C. N. Rensen. Inhibition of the central melanocortin system ...

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Section: Discussionmentioning

confidence: 99%

Inhibition of the central melanocortin system decreases brown adipose tissue activity

Kooijman

Boon

Parlevliet

et al. 2014

Journal of Lipid Research

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“…Leptin might regulate intestinal MTP expression through the melanocortin pathway. Recent data suggest that leptin-melanocortin pathway may modulate intestinal MTP metabolism and intestinal lipid absorption (19).…”

Section: Discussionmentioning

confidence: 99%

Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease

Cheung

Mak

2012

American Journal of Physiology-Renal Physiology

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Aberrant melanocortin signaling has been implicated in the pathogenesis of wasting in chronic kidney disease (CKD). Previously, we demonstrated that agouti-related peptide (AgRP), a melenocortin-4 receptor antagonist, reduced CKD-associated cachexia in CKD mice. Our previous studies with AgRP utilized dual energy X-ray (DXA) densitometry to assess the body composition in mice (Cheung W, Kuo HJ, Markison S, Chen C, Foster AC, Marks DL, Mak RH. J Am Soc Nephrol 18: 2517–2524, 2007; Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH. J Clin Invest 115: 1659–1665, 2005). DXA is unable to differentiate water content in mice, and fluid retention in CKD may lead to an overestimate of lean mass. In this study, we employed quantitative magnetic resonance technique to evaluate body composition change following central administration of AgRP in a CKD mouse model. AgRP treatment improved energy expenditure, total body mass, fat mass, and lean body mass in CKD mouse. We also investigated the effect of CKD-associated cachexia on the signaling pathways leading to wasting in skeletal muscle, as well as whether these changes can be ameliorated by central administration of AgRP. AgRP treatment caused an overall decrease in proinflammatory cytokines, which may be one important mechanism of its effects. Muscle wasting in CKD may be due to the activation of proteolytic pathways as well as inhibition of myogenesis and muscle regeneration processes. Our results suggest that these aberrant pathological pathways leading to muscle wasting in CKD mice were ameliorated by central administration of AgRP.

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“…2C , Table 2 ). This latter fi nding is likely attributable to a decrease in intestinal cholesterol absorption, because intestinal mRNA expression of NPC1L1 was 50% lower in mice receiving MTP inhibitor ( Table 1 ), and patients with abetalipoproteinemia lacking intestinal MTP ( 4, 10 ) as well as intestinespecifi c MTP knockout mice exhibit decreased intestinal lipid absorption ( 14,33 ). Consistent with this hypothesis, subsequent determination of intestinal cholesterol absorption confi rmed a 46% decrease in the mice treated with the pharmacological MTP inhibitor (48.1 ± 4.0% vs. 25.9 ± 1.7%, P < 0.001).…”

Section: Systemic Mtp Inhibition Does Not Impact Biliary Sterol Secrementioning

confidence: 99%

Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice

Dikkers

Annema

Boer

et al. 2014

Journal of Lipid Research

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Cholesterol within apoB-containing lipoproteins is a major risk factor for the development of atherosclerotic CVD ( 1, 2 ). Plasma levels of apoB-containing lipoproteins are determined by hepatic production in the form of VLDLs and intestinal production of chylomicrons, in which cholesterol absorbed from the diet is packaged ( 3-5 ). For the assembly of both forms of apoB-containing lipoproteins, microsomal triglyceride transfer protein (MTP) expression is essential ( 4, 5 ). This is exemplifi ed by reduced secretion of apoBcontaining lipoproteins and the subsequent accumulation of hepatic triglycerides when MTP is absent in rodent models ( 6-9 ) or in human abetalipoproteinemia, a genetic disease characterized by MTP defi ciency ( 10 ). On the other hand, overexpression of MTP increases secretion of apoBcontaining lipoproteins ( 11, 12 ). Deletion of MTP, specifically in the intestine, was shown to reduce plasma cholesterol levels by about 45-50% ( 13, 14 ), illustrating the contribution of the intestine to systemic lipoprotein metabolism. The key role of MTP in determining circulating levels of apoB-containing lipoproteins and their importance for atherosclerotic CVD resulted in the development of systemically active pharmacological inhibitors that have recently entered phase 3 clinical trials ( 15, 16 ). Although a variable increase in hepatic triglyceride content was noticed, MTP inhibitors seem to have a reasonable safety profi le and thus Abstract Because apoB-containing lipoproteins are proatherogenic and their secretion by liver and intestine largely depends on microsomal triglyceride transfer protein (MTP) activity, MTP inhibition strategies are actively pursued. How decreasing the secretion of apoB-containing lipoproteins affects intracellular rerouting of cholesterol is unclear. Therefore, the aim of the present study was to determine the effects of reducing either systemic or liver-specifi c MTP activity on cholesterol metabolism and reverse cholesterol transport (RCT) using a pharmacological MTP inhibitor or a genetic model, respectively. Plasma total cholesterol and triglyceride levels were decreased in both MTP inhibitortreated and liver-specifi c MTP knockout (L-Mttp ؊ / ؊ ) mice (each P < 0.001). With both inhibition approaches, hepatic cholesterol as well as triglyceride content was consistently increased (each P < 0.001), while biliary cholesterol and bile acid secretion remained unchanged. A small but significant decrease in fecal bile acid excretion was observed in inhibitor-treated mice ( P < 0.05), whereas fecal neutral sterol excretion was substantially increased by 75% ( P < 0.001), conceivably due to decreased intestinal absorption. In contrast, in L-Mttp ؊ / ؊ mice both fecal neutral sterol and bile acid excretion remained unchanged. However, while total RCT increased in inhibitor-treated mice ( P < 0.01), it surprisingly decreased in L-Mttp ؊ / ؊ mice ( P < 0.05). These data demonstrate that: i ) pharmacological MTP inhibition increases RCT, an effect that might provide additional cli...

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An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption

Cited by 55 publications

References 79 publications

Inhibition of the central melanocortin system decreases brown adipose tissue activity

Inhibition of the central melanocortin system decreases brown adipose tissue activity

Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease

Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice

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