1. Obesity and Cancer: The Oil that Feeds the Flame
Joan Font-Burgada, Beicheng Sun, Michael Karin 
Cell Metabolism 
Volume 23, Issue 1, Pages (January 2016)
DOI: /j.cmet
Copyright © 2016 Elsevier Inc. Terms and Conditions

2. Figure 1 Systemic Mechanisms of Obesity-Driven Tumor Promotion
Obesity and hypernutrition affect different tissues simultaneously resulting in a systemic increase in NEFA, insulin, glucose, leptin and inflammatory cytokines, and reduced levels of adiponectin. These imbalances can directly promote cancer cell survival, proliferation, and malignant progression. In the colon, obesity can promote a shift in the composition of the microbiota that is linked to higher epithelial permeability to microbial components such as LPS, which in turn enhances local inflammation. In adipose tissue, obesity is linked to adipocyte hyperplasia and hypertrophy followed by infiltration of inflammatory macrophages. The inflammatory milieu thus generated reprograms the tissue to release NEFA, produce more leptin, and less adiponectin. The liver, exposed to microbial products from the colon via the portal circulation, also mounts a low-grade inflammatory response. Higher amounts of NEFA from adipose tissue lead to an increased lipid storage and elevated lipogenesis. The consequence of local inflammation and lipid accumulation is liver insulin resistance and hepatocyte stress and death. Finally, the pancreas reacts to hepatic insulin resistance and higher glycemia with increased insulin production, which can lead to β-cell stress.
Cell Metabolism  , 48-62DOI: ( /j.cmet )
Copyright © 2016 Elsevier Inc. Terms and Conditions

3. Figure 2 Mechanisms of Obesity-Induced HCC
Two main pathways converge to drive ER stress in the obese liver. On one hand, microbial products from the intestine reach the liver via the portal vein. Liver-resident macrophages activate an inflammatory response that includes iNOS expression, which results in S-nitrosylation of IRE1α, thereby compromising the UPR and consequently leading to ER stress. On the other hand, high amounts of nutrients activate mTORC1 signaling leading to phosphorylation of CRTC2, freeing SEC31 and allowing the activation of the SEC31/32 complex that processes SREBP1. Processed SREBP1 translocates into the nucleus and activates the lipogenic program, thereby aggravating the lipid accumulation and inducing severe hepatic steatosis with consequent lipotoxicity, ROS generation, and ER stress. At the same time, newly synthesized lipids change the composition of the ER membrane and inhibit the sarco/endoplasmic reticulum calcium ATPase (SERCA) activity producing a decrease of Ca2+ aggravating ER stress. Both pathways synergistically cooperate to drive hepatocyte cell death, while ROS buildup in liver cells promotes mutagenesis and genomic instability. Importantly, cell death increases tissue inflammation and supports a positive feedback loop that extends liver damage and compensatory proliferation. When this becomes chronic, it leads to HCC development.
Cell Metabolism  , 48-62DOI: ( /j.cmet )
Copyright © 2016 Elsevier Inc. Terms and Conditions

4. Figure 3 Mechanisms of Obesity-Promoted PDAC
Defective autophagy in pancreatic acinar cells leads to toxic accumulation of p62 aggregates, inducing ER stress and eventual cell death. Established inflammation and NRF2 activation cause the metaplasia of surviving acinar cells and converts them to a ductal progenitor phenotype, thereby generating low-grade PanIN. To convert low-grade PanIN lesions into PDAC, metabolic reprogramming is needed through the action of members of the MITF/TFE family of transcription factors, which upregulate autophagy, to promote cell survival. Other metabolic changes promote proliferation within PanIN lesions and lead to PanIN to PDAC progression.
Cell Metabolism  , 48-62DOI: ( /j.cmet )
Copyright © 2016 Elsevier Inc. Terms and Conditions

5. Figure 4 Mechanisms of Obesity-Induced CRC
Obesity induces dysbiosis and thinning of the intestinal mucus layer resulting in increased permeability of the intestinal epithelium to microbial products. Resident immune cells react to these inflammatory cues by secreting a cocktail of inflammatory cytokines that act directly on cancer progenitor cells to stimulate their survival and proliferation. Obesity-associated microbial dysbiosis can result in elevated concentrations of metabolites that further contribute to tumor promotion. High levels of circulating IGF-1, insulin and inflammatory cytokines, and reduced levels of adiponectin also contribute to promotion of CRC development.
Cell Metabolism  , 48-62DOI: ( /j.cmet )
Copyright © 2016 Elsevier Inc. Terms and Conditions