Abstract
(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance.
Highlights
During times of nutrient scarcity, having sufficient storage capacity to cope with changes in dietary calorie intake is important [1]
While several studies have demonstrated that a high-fat diet (HFD) diet increases thermogenic activity through sympathetic stimulation in brown adipose tissue (BAT) [9], others have demonstrated suppressed adrenergic signaling with downregulated mitochondrial biogenesis in a single fat cell or in white and brown adipose tissue depots [10]
We showed that while mitochondrial biogenesis and thermogenic capacity markers were retained in both SAT and BAT at 6 weeks of HFD, less-pronounced effects were seen in EPI
Summary
During times of nutrient scarcity, having sufficient storage capacity to cope with changes in dietary calorie intake is important [1]. Current dietary habits and the availability of cheap and calorie-dense food in modern society has disrupted this balance [1,3] and led to an alarming increase in the prevalence of obesity type 2 diabetes and insulin resistance worldwide [4]. The increase in fat deposition in ectopic tissues can result in tissue inflammation, insulin resistance, and systemic metabolic dysfunction [2], but as we and others have found, there are many unanswered questions linking the dynamics and time course of adipose tissue dysfunction with ectopic lipid deposition and the advent of impaired insulin action [5,6]. It remains unclear if therapy that increased beiging of fat would be effective in combating the long-term effects of HFD (>14 weeks), as studies on mitochondrial biogenesis and thermogenesis in adipose tissue have been inconclusive. Clarification as to whether divergent results were due to: (1) differences in the choice or in the diversity and number of fat depots studied; (2) differences in time course; or (3) differences in the responses of selected white adipose tissue depots is clearly needed
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