You deserve what you eat: lessons learned from the study of the melanin-concentrating hormone (MCH)-deficient mice.
OBJECTIVE
Diet plays a crucial role in the development of obesity and insulin resistance via multiple mechanisms. Saturated fatty acids can directly trigger tissue specific proinflammatory pathways via Toll-like receptor-4 (TLR4)-dependent mechanisms. Moreover, diet can change the gut microbiome and increase gut permeability. However, very few studies have addressed the obesity-independent role of diet. Dissecting the effects of diet from those of obesity per se will enhance our understanding of the underlying pathogenesis, and, at the translational level, advance our treatment approaches for obesity and its co-morbidities.


METHODS
Melanin-concentrating hormone (MCH) is an important regulator of appetite and energy balance. MCH-deficient mice are resistant to diet-induced obesity, primarily due to increased locomotor activity. We took advantage of the unique phenotype of these mice to examine the metabolic and inflammatory consequences of a 15-week consumption of a diet high in saturated fat.


RESULTS
MCH-deficient mice chronically exposed to a high-fat diet gain less weight compared to their wild-type littermates, despite similar food intake, and are protected from hepatosteatosis. They also lack obesity-associated upregulation of serum leptin and insulin levels and have improved total body insulin sensitivity. Nevertheless, we found indistinguishable liver-specific innate immune responses in both genotypes associated with high-fat feeding, which involved activation of TLR4 and its downstream effectors, MyD88, p38 MAP kinase and STAT-3.


CONCLUSIONS
Our findings indicate that high-fat feeding is deleterious to the liver, independently of the obesity status. They also suggest that MCH is not necessary for the TLR4-dependent immune response triggered by the high-fat diet.
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Yan
Y
Wang
Dimitrios C
DC
Ziogas
Sudha
S
Biddinger
Efi
E
Kokkotou
D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage* / Q000494:pharmacology; D004435:Eating / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D005951:Glucose Tolerance Test; D007028:Hypothalamic Hormones / Q000172:deficiency* / Q000502:physiology; D007113:Immunity, Innate; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D050155:Lipogenesis / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010907:Pituitary Hormones / Q000172:deficiency* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013851:Thinness / Q000378:metabolism / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D007028:Hypothalamic Hormones; D007328:Insulin; D020738:Leptin; D008543:Melanins; D010907:Pituitary Hormones; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C019463:melanin-concentrating hormone