The pro-opiomelanocortin (POMC) neurons have an anorexigenic action and, when activated, reduce food intake through the release of two peptides, α-melanocyte-stimulating hormone (α-MSH) and cocaine-and-amphetamine-regulated transcripts (CART). The neuropeptide Y (NPY) neurons, on the other hand, release NPY hormone and agouti gene-related protein (AgRP), which prevent the binding of α-MSH to MC3R and MC4R, increasing food intake
This suggests that the central anorexic effects of E2 may occur via ERβ
The main hypothalamic areas involved in food intake and satiety are the arcuate nucleus (ARC), the lateral hypothalamus (LH), the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), and the dorsomedial hypothalamus (DMH)
Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure
E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution
ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake
It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.
Both ERs have been identified in the ARC
Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.
Both ERs have been identified in the LH
both ERs have been identified in this nucleus
The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive
The VMH is ERα regulated
Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body
GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake
data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance
In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane
It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.
E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue
In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue
decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin
Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance
Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs
Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue
suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue
very nice article that looks at the balance of ER-alpha/ER-beta and their role in metabolic syndrome. This article discusses the balance of these receptors are tissue dependent in their effect. I like their conclusion: "...but these mechanisms will never be completely understood if they are not considered in the context of a whole system.
Activation of the innate immune system controls macronutrient metabolism
the innate immune response is the first line of defense against invading pathogens, wherein highly conserved pathogen-associated molecular patterns (PAMPs) are recognized by cognate pattern recognition receptors (PRRs
many studies have supported the idea that cytokine signaling directly promotes insulin resistance
innate immune system may be causally linked to obesity
adipose tissue contains a substantial population of macrophages, and macrophage-driven adipose inflammation contributes significantly to the pathogenesis of obesity
Collectively, activation of the innate immune system is strongly associated with ASCVD, insulin resistance, and obesity, and recent evidence suggests that much of this association can be traced to a unique family of PRRs known as TLRs
TLRs are a family of type I transmembrane receptors, currently thought to comprise at least 13 members in mammals, that specifically recognize a variety of microbial PAMPs and trigger host cellular responses
Free SFAs have indeed been demonstrated to elicit TLR4-dependent and TLR2-dependent responses in several cell types.
Endogenous SFAs released from adipocytes activate cocultured macrophages via TLR4 [18], indicating the potential for cellular crosstalk in adipose tissue. Collectively, there is a growing body of evidence that SFAs promote, whereas long chain PUFA antagonize, TLR4-dependent and TLR2-dependent signaling in multiple cell models
In an elegant study, Shi et al. [16] demonstrated that SFAs activate TLR4-dependent signaling in both macrophages and adipocytes, and mice lacking TLR4 are protected against insulin resistance driven by intravenous lipid infusion
In addition to effects in macrophages and adipocytes, SFAs can activate TLR4 in the hypothalamus, which triggers a central inflammatory response that results in resistance to anorexigenic signals
endogenous SFAs can indeed promote innate immunity and inflammatory disease
This finding strongly supports the work of Hwang and coworkers [19–22] demonstrating that ω-3 PUFAs can effectively counteract SFA-induced TLR4 activation in cultured macrophages and dendritic cells.
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.