Developing non-cognitive approaches for treating obesity is imperative. We have been using gnotobiotic mice to examine the significance of human-bacterial symbioses in the gut, and discovered that the intestinal microbiota has a remarkable effect on fat storage. Colonization ('conventionalization') of adult germ-free (GF) C57B1/6 (B6) mice with a cecal microbiota harvested from conventionally-raised mice produces a 60% increases in total body fat content and white adipose tissue (WAT) weight. This rapid increase occurs despite decreased chow consumption and increased metabolic rate, is sustained, and accompanied by increased leptin levels, insulin resistance, and increased hepatic lipogenesis. The lipogenic response is associated with increased nuclear import of carbohydrate response element binding protein (ChREBP), modest increases in insulin-responsive SREBP-1, and trans-activation of ChREBP/SREBPl lipogenic gene targets. WAT hypertrophy is associated with increased LPL activity and intestine-specific transcriptional suppression of Fiaf (encodes a secreted LPL inhibitor). Moreover, GF Fiaf knockout mice have higher WAT LPL activity and the same body fat content as 'conventionalized' (Fiaf-suppressed) wild-type (wt) littermates: their fat stores are not increased further with conventionalization. These results suggest the following testable hypothesis: (a) microbial processing of otherwise indigestible dietary polysaccharides (PS) provides monosaccharides that lead to ChREBP, and possibly, SREBP-1- stimulation of hepatic lipogenesis: (b) microbial suppression of intestinal Fiaf, combined with the lipogenic response, promotes LPL-mediated increases in adipocyte fat storage; (c) increasing Fiaf expression and/or activity should promote leanness.
Aim 1 - Use wt B6 mice to determine the role of dietary carbohydrates and microbial ecology on microbiota-induced fat storage. GF and conventionalized mice will be fed isocaloric high PS/low fat, .high fat/low PS, or high sugar/low fat diets, and the effects on body fat content, VO2, feptin/glucose/insulin, WAT LPL, and intestine/liver/muscle energy metabolism assayed. Microbial requirements will be assessed by colonization with all or some components of a simplified 8-member microbiota (Altered Schaedler Flora).
Aim 2 - Determine the contribution of the microbiota-associated hepatic lipogenic response by conventionalizing GF mice with a ChREBP knockout, a SREBP-1 c knockout, combined ChREBP and SREBP-1 c deficiencies, or a hepatocyte-specific Fasl knockout.
Aim 3 - Introduce a transgene constitutively expressed in the small intestinal epithelium into Fiaf-/- mice. We predict that these mice will phenocopy leaner GF wt mice, whether or not they have been colonized [proof-of-concept genetic test of whether therapeutic manipulations that increase Fiaf expression (or activity) will promote leanness].
| Mark Welch, Jessica L; Hasegawa, Yuko; McNulty, Nathan P et al. (2017) Spatial organization of a model 15-member human gut microbiota established in gnotobiotic mice. Proc Natl Acad Sci U S A 114:E9105-E9114 |
| Green, Jonathan M; Barratt, Michael J; Kinch, Michael et al. (2017) Food and microbiota in the FDA regulatory framework. Science 357:39-40 |
| Barratt, Michael J; Lebrilla, Carlito; Shapiro, Howard-Yana et al. (2017) The Gut Microbiota, Food Science, and Human Nutrition: A Timely Marriage. Cell Host Microbe 22:134-141 |
| Griffin, Nicholas W; Ahern, Philip P; Cheng, Jiye et al. (2017) Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions. Cell Host Microbe 21:84-96 |
| Charbonneau, Mark R; O'Donnell, David; Blanton, Laura V et al. (2016) Sialylated Milk Oligosaccharides Promote Microbiota-Dependent Growth in Models of Infant Undernutrition. Cell 164:859-71 |
| Semenkovich, Nicholas P; Planer, Joseph D; Ahern, Philip P et al. (2016) Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes. Proc Natl Acad Sci U S A 113:14805-14810 |
| Wu, Meng; McNulty, Nathan P; Rodionov, Dmitry A et al. (2015) Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides. Science 350:aac5992 |
| Rosenbaum, Michael; Knight, Rob; Leibel, Rudolph L (2015) The gut microbiota in human energy homeostasis and obesity. Trends Endocrinol Metab 26:493-501 |
| Subramanian, Sathish; Blanton, Laura V; Frese, Steven A et al. (2015) Cultivating healthy growth and nutrition through the gut microbiota. Cell 161:36-48 |
| Faith, Jeremiah J; Colombel, Jean-Frédéric; Gordon, Jeffrey I (2015) Identifying strains that contribute to complex diseases through the study of microbial inheritance. Proc Natl Acad Sci U S A 112:633-40 |
Showing the most recent 10 out of 53 publications
