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Cymbalta Weight Gain

Cymbalta has been a popular antidepressant for several decades and Cymbalta weight gain has been overlooked by the healthcare industry. It is normal for 55% of those taking Cymbalta to experience weight gain. Unfortunately, 40.6 percent of the people taking Cymbalta will gain 7% or more weight, the health concerns are real. (1)

Further studies are listed below but The Harper Method has one interest; helping those that have Cymbalta weight gain and losing the weight safely.

Who is this method for?

It is for those who may or may not want to stay on Cymbalta

It is also for those that are now off Cymbalta

It is for those that have gained weight due to Cymbalta

It is for those that have tried to diet and exercise and the Cymbalta weight gain will not come off

How this method works

You need to start reducing the activation of the JNK gene. The JNK gene is associated with weight gain and all antidepressants induce the activation of the JNK gene. Until you do this; all of the exercise and dieting in the world will be of no use.

How this is done is simple. After 22 years of research two supplements have been formulated in reduce the activation of the JNK1, JNK 2 and to slightly reduce the activation of the JNK 3. Additionally, other proteins that reside upstream of the JNK's need to be silenced and these are silenced with the supplements as well.

Foods; you should start eliminating foods with preservatives as your first diet change.

Exercise; if you do not get any exercise, it is time to start with walking. At least 3 walks a week, with each walk for 20 minutes.

The two supplements setup your body to lose the weight gain caused by Cymbalta but you also need to do the normal things that help you lose weight; diet and exercise.

I am assuming you have already tried diet and exercise without Cymbalta weight loss success.

The Method gives the full steps in sequence for how to reverse the Cymbalta weight gain. Click here.

(1)  Jan-Feb 2015;37(1):46-8.

doi: 10.1016/j.genhosppsych.2014.10.011. Epub 2014 Oct 31.

Weight gain and associated factors in patients using newer antidepressant drugs

Objective: The aim of the present study was to examine weight gain and its association with clinical and sociodemographic characteristics in patients using newer antidepressants.

Methods: The study had a cross-sectional design. A total of 362 consecutive psychiatric patients taking antidepressant drugs for 6 to 36 months were included in the study.

Results: The prevalence rate of weight gain was 55.2%; 40.6% of the patients had a weight gain of 7% or more compared to the baseline. Overall, antidepressant use was significantly related to increased body weight. Specifically, citalopram, escitalopram, sertraline, paroxetine, venlafaxine, duloxetine and mirtazapine, but not fluoxetine, were associated with significant weight gain. Multivariate logistic regression analysis indicated that lower education status, lower body mass index at the onset of antidepressant use and family history of obesity were independent predictors of weight gain ≥7% compared to the baseline.

Conclusions: The study results suggest that patients who take newer antidepressants might have significant problems related to body weight.

Keywords: Antidepressants; Body mass index; Weight gain.

(2) JNK at the crossroad of obesity, insulin resistance, and cell stress response

Background: The cJun-N-terminal-kinase (JNK) plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival, depending on the specific context. JNK is also one of the most investigated signal transducers in obesity and insulin resistance, and studies have identified new molecular mechanisms linking obesity and insulin resistance. Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the development of obesity and insulin resistance, JNK3 activity protects from excessive adiposity. Furthermore, current evidence indicates that JNK activity within specific cell types may, in specific stages of disease progression, promote cell tolerance to the stress associated with obesity and type-2 diabetes.

Scope of review: This review provides an overview of the current literature on the role of JNK in the progression from obesity to insulin resistance, NAFLD, type-2 diabetes, and diabetes complications.

Major conclusion: Whereas current evidence indicates that JNK1/2 inhibition may improve insulin sensitivity in obesity, the role of JNK in the progression from insulin resistance to diabetes, and its complications is largely unresolved. A better understanding of the role of JNK in the stress response to obesity and type-2 diabetes, and the development of isoform-specific inhibitors with specific tissue distribution will be necessary to exploit JNK as possible drug target for the treatment of type-2 diabetes.

Keywords: Autophagy; Diabetes; Endoplasmic eeticulum stress; Inflammation; MAPK; Oxidative stress.

(3) Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes

Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.

Keywords: JNK; c-Jun N-terminal kinase; glucotoxicity; inflammation; insulin resistance; lipotoxicity; obesity; type 2 diabetes.

(4) Adipocyte-Macrophage Cross-Talk in Obesity

Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction has a primary importance in obesity. Large amounts of macrophages are accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway also promotes more macrophage accumulation into the obese adipose tissue. However, increased local extracellular lipid concentrations is a final mechanism for adipose tissue macrophage accumulation. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-alpha) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1beta) by macrophages; both adipocyte and macrophage induction by toll like receptor-4 (TLR4) through nuclear factor-kappaB (NF-kappaB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in macrophage accumulation and in the development of adipose tissue inflammation. Old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. The obesity-induced changes in adipose tissue macrophage numbers are mainly due to increases in the triple-positive CD11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. The ratio of M1-to-M2 macrophages is increased in obesity. Furthermore, hypoxia along with higher concentrations of free fatty acids exacerbates macrophage-mediated inflammation in obesity. The metabolic status of adipocytes is a major determinant of macrophage inflammatory output. Macrophage/adipocyte fatty-acid-binding proteins act at the interface of metabolic and inflammatory pathways. Both macrophages and adipocytes are the sites for active lipid metabolism and signaling.

Keywords: C-C chemokine receptor 2 (CCR2); Chemokine (C-C motif) ligand 2 (CCL2); Free fatty acids; Hypoxia-inducible factor-1 alpha (HIF-1alpha); Insulin-like growth factor-1 (IGF1); Interleukin-6 (IL-6); M1 macrophages; M2 macrophages; Monocyte chemoattractant protein-1 (MCP-1); NOD-like receptor (NLR) family protein (NLRP3); Obesity; Toll like receptor 4 (TLR4); Tumor necrosis factor-alpha (TNF-alpha); Visceral adipose tissue.

(5) The Role of JNk Signaling Pathway in Obesity-Driven Insulin Resistance

Obesity is not only closely related to insulin resistance but is one of the main factors leading to the formation of Type 2 Diabetes (T2D) too. The c-Jun N-terminal kinase (JNK) family is a member of the mitogen-activated protein kinase (MAPK) superfamily. JNK is also one of the most investigated signal transducers in obesity and insulin resistance. JNK-centric JNK signaling pathway can be activated by growth factors, cytokines, stress responses, and other factors. Many researches have identified that the activated phosphorylation JNK negatively regulates insulin signaling pathway in insulin resistance which can be simultaneously regulated by multiple signaling pathways related to the JNK signaling pathway. In this review, we provide an overview of the composition of the JNK signaling pathway, its regulation of insulin signaling pathway, and the relationship between the JNK signaling pathway and other pathways in insulin resistance.

Keywords: JNK signaling pathway; insulin resistance; obesity; type 2 diabetes.

(6) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation

The cJun NH(2)-terminal kinase (JNK) signaling pathway contributes to inflammation and plays a key role in the metabolic response to obesity, including insulin resistance. Macrophages are implicated in this process. To test the role of JNK, we established mice with selective JNK deficiency in macrophages. We report that feeding a high-fat diet to control and JNK-deficient mice caused similar obesity, but only mice with JNK-deficient macrophages remained insulin-sensitive. The protection of mice with macrophage-specific JNK deficiency against insulin resistance was associated with reduced tissue infiltration by macrophages. Immunophenotyping demonstrated that JNK was required for pro-inflammatory macrophage polarization. These studies demonstrate that JNK in macrophages is required for the establishment of obesity-induced insulin resistance and inflammation.

(7) The Pathogenesis of Obesity-Associated Adipose Tissue Inflammation

Obesity is characterized by a state of chronic, low-grade inflammation. However, excessive fatty acid release may worsen adipose tissue inflammation and contributes to insulin resistance. In this case, several novel and highly active molecules are released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines. Most likely cytokines that are released by inflammatory cells infiltrating obese adipose tissue are such as tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2) and IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation. In this process, toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress through hyperactivation of c-Jun N-terminal Kinase (JNK) -Activator Protein 1 (AP1) and inhibitor of nuclear factor kappa-B kinase beta (IKKbeta)-nuclear factor kappa B (NF-kappaB) pathways play an important role, and may also affect vascular endothelial function by modulating vascular nitric oxide and superoxide release. Additionally, systemic oxidative stress, macrophage recruitment, increase in the expression of NOD-like receptor (NLR) family protein (NLRP3) inflammasone and adipocyte death are predominant determinants in the pathogenesis of obesity-associated adipose tissue inflammation. In this chapter potential involvement of these factors that contribute to the adverse effects of obesity are reviewed.

Keywords: Adipose tissue macrophages (ATMs); Autophagy; Ceramide; Endoplasmic reticulum stress; Inducible nitric oxide synthase (iNOS); Lipotoxicity; M1 adipose tissue macrophages; Macrophage migration inhibitory factor (MIF); Monocyte chemoattractant protein 1 (MCP-1); Nuclear factor kappa B (NF-kappaB); Obesity; Reactive oxygen species (ROS); Saturated fatty acid; Toll-like receptor 4 (TLR4); Tumor necrosis factor alpha (TNF-alpha); Vascular endothelial growth factor (VEGF).

(8) Human Protein Kinases and Obesity

The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity, and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified by the target amino acid in their substrates. Some protein kinases can phosphorylate both serine/threonine, as well as tyrosine residues. This group of kinases has been known as dual specificity kinases. Unlike the dual specificity kinases, a heterogeneous group of protein phosphatases are known as dual-specificity phosphatases. These phosphatases remove phosphate groups from tyrosine and serine/threonine residues on their substrate. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases. The protein kinase-phosphoproteins interactions play an important role in obesity . In obesity, the pro- and anti-inflammatory effects of adipokines and cytokines through intracellular signaling pathways mainly involve the nuclear factor kappa B (NF-kappaB) and the c-Jun N-terminal kinase (JNK) systems as well as the inhibitor of kappaB-kinase beta (IKK beta). Impairment of insulin signaling in obesity is largely mediated by the activation of the IKKbeta and the JNK. Furthermore, oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2alpha kinase (PERK) and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. Increase in intracellular oxidative stress can promote PKC-beta activation. Activated PKC-beta induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhances triglyceride accumulation. Obesity is fundamentally caused by cellular energy imbalance and dysregulation. Like adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), N-terminal Per-ARNT-Sim (PAS) kinase are nutrient responsive protein kinases and important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states.

Keywords: Adenosine monophosphate (AMP)-activated protein kinase (AMPK); Dual specificity kinases; Extracellular signal-regulated protein kinase (ERK); Inhibitor of kappaB-kinase (IKK); Lipoapoptosis; Liver kinase B1 (LKB1); MAPK phosphatases; Mammalian target of rapamycin (mTOR); Mitogen-activated protein kinases (MAPK); N-terminal Per-ARNT-Sim (PAS) kinase (PASK); Protein kinase B (Akt); Protein kinase-like endoplasmic reticulum (ER) eukaryotic initiation factor-2alpha kinase (PERK); Protein kinases; Protein phosphatases; c-Jun N-terminal kinase (JNK).