Another strategy that has been proposed for the treatment of obesity is to inhibit pancreatic lipase, which consequently decreases lipid absorption in the intestine
[77][19]. The underlying concept is that for any dietary fat being absorbed in the human intestine, the fat should be broken down enzymatically by the action of pancreatic lipase
[78][20]. Pancreatic lipase activity is therefore widely considered as one of the most important indicators for the determination of the anti-obesity potential of natural products
[79][21]. Orlistat, a potent, specific, and irreversible inhibitor of pancreatic and gastric lipases, is a weight-loss agent with a novel mechanism of action for the treatment of obesity. It inhibits gastric and pancreatic lipases in the lumen of the gastrointestinal tract to decrease systemic absorption (30%) of dietary fat
[80][22]. However side effects such as diarrhea, fecal incontinence, flatulence, bloating and dyspepsia are commonly developed
[11][23]. Due to these adverse effects, there has been a long-standing interest in discovering well-tolerated natural inhibitors for nutrient digestion and absorption.
The potential inhibitory activity against pancreatic lipase was also reported by examining the effect of HSE on fat absorption-excretion and body weight in rats
[12][8]. Thus, continuous administration of
H. sabdariffa polyphenols might improve obesity-related metabolic disorders in a similar manner to orlistat
[36][24]. While this action may be viewed as a potential strategy in obesity management, its mechanism in obesity therapy is yet to be explored.
4. Effect of HSE on Adipocyte Differentiation (Adipogenesis)
Adipogenesis is the process by which cells differentiate into adipocytes. This process involves the conversion of preadipocytes into mature adipocytes with intracellular lipid accumulation
[81][25]. Adipocytes are cells that primarily compose adipose tissue, specialized in storing energy as fat
[82][26]. They play an important role in regulating adipokine secretion which promotes adipogenesis. Therefore, understanding the molecular mechanisms that regulate adipogenesis is important for exploring anti-obesity therapy
[83][27].
Adipocyte differentiation is a critical phenomenon in the development and progression of obesity
[84][28]. Adipocyte differentiation has been reported to be mainly mediated by the transcription factors PPARγ and C/EBPα
[81][25]. These adipogenic transcription factors that are implicated to activate a number of genes induced during adipocyte differentiation is a master regulator of adipogenesis
[85,86,87][29][30][31]. Hence, a down-regulation of PPARγ and C/EBPα has been viewed as a strategy to obstruct adipogenesis in adipocytes. Several studies have reported that extract of various medicinal plants attenuates expression of PPARγ and C/EBPα
[10,61,88,89,90,91][32][4][33][34][35][36].
So far, only a few studies have reported and confirmed the effect of HSE on adipocyte differentiation. Kim et al.,
[68][37] first reported the effect of HSE treatment on adipocyte differentiation from 3T3-L1 preadipocytes and found that HSE blocked adipogenesis, possibly mediated through the suppression of adipogenic transcription factor expression. HSE treatment (100 mg/mL) inhibited the expression of major adipogenic transcription factors PPAR-γ and C/EBP-α, nuclear hormone receptors that regulate adipogenesis during differentiation. The authors further stated that this inhibitory effect of HSE on the transcription factors was target specific
[68][37]. Further studies by Kim et al.
[10][32], also confirmed that HSE can inhibit the adipogenic transcription factors by blocking the MAPK-mediated signaling pathway during adipocyte differentiation. They reported that HSE significantly decreased the mRNA levels of leptin (a hormone predominantly made by adipose cells that helps to regulate energy balance) during differentiation. Hence, suggesting that the effect of HSE on adipocyte differentiation was also mediated by the regulation of leptin
[10][32].
A recent study performed on 3T3-L1 pre-adipocytes cells revealed that
H. sabdariffa aqueous extract and
H. sabdariffa polyphenols at concentrations 500 µg/mL and 10 µg/mL significantly inhibited adipogenic differentiation of pre-adipocytes
[58][38]. These authors concluded that polyphenols contained in
H. sabdariffa are mainly accountable for its effect on adipogenesis. Kao et al.
[8][17], also showed that
H. sabdariffa polyphenolic extract (HPE) was more efficient in suppressing adipogenesis than HSE as markers of adipocyte differentiation, while SREBP 1 was found to decrease in a concentration-dependent manner following treatment with both HSE and HPE. The authors reported in their study that after inducing maturation of preadipocyte, HPE suppressed the adipogenesis of mature adipocyte cells. This corroborates with the previously reported findings that polyphenols are the major active components in HSE that are responsible for its anti-obesogenic effect.