Wednesday, December 26, 2012

Seabuckthorn Leaves Increase PPAR-Alpha & PPAR-Gamma Expression, Keep the Liver Fat Free and Fatty Oxidation Up. Plus: PPARs - High or Low? How Are They Supposed to Be?

This time, the magic is in the leaves, not the fruits or kernels. And it's dose dependent. With an almost linear increase from 500-1,000mg/kg
Honestly, I don't think that it is coincidence that many of the most promising medical plants are shrubs that live on barren soil, like sand dunes and cliffs and are full of thorns as well as innate polyphenolic defense mechanisms. Whatever the "evolutionary" basis may be, if we go by the beneficial metabolic effects, researchers from the Department of Food Science and Human Nutrition at the Chonbuk National University in the Republic of Korea, it appears worth going through all the traditional used folk medicine across the world and identify which of them work, how they work and whether they may already have what it takes to get rid of one or the other of the typical Western diseases.

In the case of the ethanolic extract of seabuckthorn (Hippophae rhamnoides L) Pichiah et al. used in their most recent experiment, this would be ameliorative effects on weight gain through down-regulation of adipogenic and lipogenic gene expression.

Less weight gain more fatty acid turnover, better glucose management and leptin sensitivity

The ameliorative effects on the detoriation of glucose metabolism, the reduced but still significant weight gain of the 60% fat diet (additional fat 100% from lard) and the profound overexpression of leptin, which is indicative of the fact that the mice developed full-blown leptin resistance within the 13-weeks of HFD administration, were all ameliorated to a greater degree in the high dose seabuckthorn leaf extract group (human equivalent  ~6.5g/day).
Figure 1: Effect of the different diets on weight gain, visceral fat weight, feed intake and energy intake (left; data expressed relative to control diet); effects on blood sugar (AUC in glucose tolerance test) and leptin (Pichiah. 2012)
The differences between high and low dose supplementation of the extract which had been prepared by
"[...] by soaking the dried, powdered leaves in 70% ethanol for 7 days at room temperature. Then the extract was concentrated by evaporating ethanol using a rotary vacuum evaporator (N-N Series, EYELA, Tokyo, JAPAN) set at 60°C and 100 hPa" (Pichiah. 2012)
were even more pronounced, when we compare the effects on fatty acid oxidation (CPT-1), the PPAR-alpha and -gamma values.
Figure 2: Carnitine palmitoyltransferase I (CPT1), PPAR-alpha & -gamma activity and triglyceride & cholesterol content in the liver (left; expressed relative to rodents on normal chow). Histology of liver sections at 200x magnification for the different diets (Pichiah. 2012)
What's yet most striking is however that the liver - the organ that's so heavily involved in the etiology of insulin resistance - was virtually "fat-free" in the rodents who received the 1,000mg/day dose. The total triglyceride and cholesterol content was even lower than in the mice on the normal diet and the overall darker staining in the slices on the right of figure 2 is only further evidence of the beneficial effects the seabuckthorn extract had on the liver histology.
The effects of a 5% conjugated linoleic acid diet do actually resemble that of lipodystrophy, i.e. pathological fat loss and inability to store body fat. Strange, no? Well that's PPAR-gamma (read more).
PPAR-gamma? Wasn't that what you actually wanted to avoid? In a way this is right, since PPAR-gamma and even alpha are somewhat Janus-faced molecules (overview for PPAR-alpha). As beneficial as their expression in the liver may be, both inhibit the oxidation of glucose. PPAR-gamma is also involved in the maturation process from pre-adipocytes to mature adipocytes, increases lipogenesis in white adipose tissues, decreases the cell surface fatty acid transporter on muscle cells and increases glucose uptake in adipocytes (exclusively). All that is healthier than fat clogging your liver, but it's not exactly something that will make you leaner if you are work out and consume a junk-free diet.

In fact, the PPAR-gamma suppressing effects of the trans-10, cis-12 isomer of conjugated linoleic acid (CLA; cf. Kennedy. 2008) are actually what what produces such profound effects, as they were observed in the study I discussed on July 22, 2012 (see link beneath the image of the mice).

TTA and fish oil are potent antagonists of liver PPAR expression. With the uncoupling and anti-inflammatory effects of TTA being the key to unleash & maintain fat-burning (read more).
Bottom line: It appears as if the liver is - once again - emerging as a central player in "sick obesity", meaning being fat and sick and not just fat. Which reminds me of yesterday's post on Gluten and the development of metabolic disease, where fatness is no criteria, at all. The expression of the "liver cleansing" PPAR-gamma enzymes on the other hand was.

This in turn reminds me of the effects of fish oil and TTA (a pan PPAR-activator), which - despite their questionable use as a long-term intervention can in fact stimulate intra-hepatic fatty acid oxidation to levels which are so high that oxidation rates in and out of itself could bring about some problems.

Other nutritional factors you should take into account are choline (a deficiency will actually cause fatty liver disease; read more about choline) or taurine. And on the endocrine side of things you want to keep an eye on optimal DHEA levels (read more about its effects on PPAR-gamma), thyroid hormones, testosterone and estrogen (Nemoto. 2000).

References
  • Kennedy A, Chung S, LaPoint K, Fabiyi O, McIntosh MK. Trans-10, cis-12 conjugated linoleic acid antagonizes ligand-dependent PPARgamma activity in primary cultures of human adipocytes. J Nutr. 2008 Mar;138(3):455-61.
  • Nemoto Y, Toda K, Ono M, Fujikawa-Adachi K, Saibara T, Onishi S, Enzan H, Okada T, Shizuta Y. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. J Clin Invest. 2000 Jun;105(12):1819-25.
  • Pichiah PB, Moon HJ, Park JE, Moon YJ, Cha YS. Ethanolic extract of seabuckthorn (Hippophae rhamnoides L) prevents high-fat diet-induced obesity in mice through down-regulation of adipogenic and lipogenic gene expression. Nutr Res. 2012 Nov;32(11):856-64.