Ghrelin, a peptide produced in the stomach and hypothalamus, stimulates
feeding and GH secretion
Centrally administered ghrelin exerts an orexigenic activity through the neuropeptide Y (NPY)
though ghrelin is predominantly produced in endocrine cells of the stomach (17, 18), it is also synthesized in the hypothalamic arcuate nucleus (1, 19), a critical region for feeding
Leptin, secreted by adipocytes in proportion to body fat mass
The saturated fatty acid palmitate (16:0) induces
NF-κB signaling through a TLR4-dependent mechanism
18:0 (stearic) and longer
saturated fatty acids as well as linolenic acid (18:3) increased proinflammatory cytokines, ER stress markers, and TLR4 activation
(SOCS)-3. A member of a protein family originally characterized as negative feedback regulators
of inflammation (13, 37), SOCS3 inhibits insulin and leptin signaling
IKKβ signaling in discrete neuronal subsets appears
to be required for both hypothalamic inflammation and excess weight gain to occur during HF feeding
the paradoxical observation that hyperphagia and weight gain occur when hypothalamic inflammation is induced
by HF feeding, yet when it occurs in response to systemic or local inflammatory processes (e.g. administration of endotoxin), anorexia and weight loss are the rule
, serves as a circulating signal of energy stores in part
by providing feedback inhibition of hypothalamic orexigenic pathways [e.g. neurons that express neuropeptide Y and agouti-related peptide (AgRP)]
and stimulating anorexigenic neurons
signals from Toll-like receptors (TLRs), evolutionarily conserved pattern recognition molecules critical for
detecting pathogens, amplified through signaling intermediates such as MyD88 activate the inhibitor of κB-kinase-β (IKKβ)/nuclear
factor-κB (NF-κB), c-Jun N-terminal kinase (Jnk) and other intracellular inflammatory signals in response to stimulation by
circulating saturated fatty acids
Energy storage occurs mainly at the level of white adipose tissue, where adipocytes secrete the anorexigenic adipokine leptin
humans and laboratory animals with leptin or insulin deficiency or resistance and/or increased ghrelin levels exhibit delayed or absent puberty and frequently display hypogonadotropic hypogonadism, which prevents fertility
Ghrelin suppresses pulsatile gonadotropin-releasing hormone (GnRH) release [14,15], thus serving as a signal to suppress reproduction in times of famine
Good, although brief, discussion of the interaction between metabolism and hormones. Kisspeptin is a GNRH secreatagogue "upstream". Insulin, Leptin, and Gherlin can inhibit GNRH through resistance and low levels. Probably a U shaped graph of optimal activity.
For thousands
of years humans consumed fructose amounting to 16–20 grams per day
daily consumptions amounting to 85–100 grams of fructose per day
Of key importance is the ability of fructose to by-pass the main regulatory
step of glycolysis, the conversion of glucose-6-phosphate to fructose 1,6-bisphosphate,
controlled by phosphofructokinase
Thus, while glucose metabolism is negatively regulated by phosphofructokinase, fructose can continuously enter the glycolytic pathway. Therefore, fructose can uncontrollably produce glucose,
glycogen, lactate, and pyruvate, providing both the glycerol and acyl portions of
acyl-glycerol molecules. These particular substrates, and the resultant excess energy
flux due to unregulated fructose metabolism, will promote the over-production of TG
(reviewed in [53]).
Glycemic excursions and insulin responses were reduced by 66% and 65%, respectively, in the fructose-consuming
subjects
reduction in circulating leptin both in the short
and long-term as well as a 30% reduction in ghrelin (an orexigenic gastroenteric hormone)
in the fructose group compared to the glucose group.
A prolonged elevation of TG was
also seen in the high fructose subjects
Both fat and fructose consumption usually results in low leptin concentrations which,
in turn, leads to overeating in populations consuming energy from these particular
macronutrients
Chronic fructose consumption reduces adiponectin responses, contributing to insulin
resistance
A definite relationship has also been found between metabolic syndrome and hyperhomocysteinemia
the liver takes up dietary fructose rapidly where it can be converted to
glycerol-3-phosphate. This substrate favours esterification of unbound FFA to form
the TG
Fructose stimulates
TG production, but impairs removal, creating the known dyslipidemic profile
the effects of fructose in promoting TG synthesis are independent
of insulinemia
Although fructose does not appear to acutely increase insulin levels, chronic exposure
seems to indirectly cause hyperinsulinemia and obesity through other mechanisms. One
proposed mechanism involves GLUT5
If FFA are not removed from tissues, as occurs in fructose fed insulin
resistant models, there is an increased energy and FFA flux that leads to the increased
secretion of TG
In these scenarios, where there is excess hepatic fatty acid uptake, synthesis and
secretion, 'input' of fats in the liver exceed 'outputs', and hepatic steatosis occurs
Carbohydrate induced hypertriglycerolemia results from a combination of both TG
overproduction, and inadequate TG clearance
fructose-induced metabolic dyslipidemia is usually accompanied
by whole body insulin resistance [100] and reduced hepatic insulin sensitivity
Excess VLDL secretion has been shown to deliver increased fatty acids and
TG to muscle and other tissues, further inducing insulin resistance
the metabolic effects of fructose occur through rapid utilization
in the liver due to the bypassing of the regulatory phosphofructokinase step in glycolysis.
This in turn causes activation of pyruvate dehydrogenase, and subsequent modifications
favoring esterification of fatty acids, again leading to increased VLDL secretion
High fructose diets can have a hypertriglyceridemic and pro-oxidant
effect
Oxidative stress has often been implicated in the pathology of insulin resistance
induced by fructose feeding
Administration of alpha-lipoic acid (LA) has been shown to prevent
these changes, and improve insulin sensitivity
LA treatment also prevents several deleterious effects of fructose feeding: the
increases in cholesterol, TG, activity of lipogenic enzymes, and VLDL secretion
Fructose has also been implicated in
reducing PPARα levels
PPARα is a ligand activated nuclear hormone
receptor that is responsible for inducing mitochondrial and peroxisomal β-oxidation
decreased PPARα expression can result in reduced oxidation, leading to cellular lipid
accumulation
fructose diets altered the structure and function of VLDL particles
causing and increase in the TG: protein ratio
LDL particle size has been found to be inversely related to TG concentration
therefore the higher TG results in a smaller, denser, more atherogenic LDL particle,
which contributes to the morbidity of the metabolic disorders associated with insulin
resistance
High fructose, which stimulates VLDL secretion, may initiate the cycle that results
in metabolic syndrome long before type 2 diabetes and obesity develop
A high flux of fructose to the liver, the main organ capable of metabolizing this
simple carbohydrate, disturbs normal hepatic carbohydrate metabolism leading to two
major consequences (Figure 2): perturbations in glucose metabolism and glucose uptake pathways, and a significantly
enhanced rate of de novo lipogenesis and TG synthesis, driven by the high flux of glycerol and acyl portions
of TG molecules coming from fructose catabolism
Fructose and metabolic syndrome. Good discussion of the impact of high fructose intake and metabolic dysfunction. This study also does a great job of highlighting the historical change of fructose intake.