Cardio-Metabolic Effects of High-Fat Diets and Their Underlying Mechanisms—A Narrative Review

Abstract

The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models—the diacylglycerol (DAG) model and the ceramide model—have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.

Obesity, Insulin Resistance, and Hyperandrogenism Mediate the Link between Poor Diet Quality and Ovarian Dysmorphology in Reproductive-Aged Women

“…The aMED diet and DASH eating plan are characterized by favorable combinations of dietary components, including high dietary fiber, refined composition, and proportion of macronutrients, vitamins, minerals, and other dietary factors with antioxidant properties, such as phenolic compounds (e.g., resveratrol) derived from complex carbohydrates [ 69 , 75 , 93 , 94 , 95 ]. Refinement in the composition and dosage of dietary carbohydrate and fiber and anti-inflammatory/oxidative properties of these diets have been shown to decrease IR, dysglycemia, hyperandrogenism, obesity, and induce satiety and weight loss in women with anovulation and abnormal ovarian morphology, such as PCOS in recent years [ 22 , 85 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ] and their respective mechanisms have been described in greater detail previously [ 94 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ]. Further, the DASH eating plan includes a low saturated fat dairy component that provides vitamin D, whereas aMED includes a fish component rich in ω-3 polyunsaturated fat and is designed to increase the ratio of monounsaturated fat to saturated fat intake.…”

Dual Effects of Lipid Metabolism on Osteoblast Function

“…Over the last decade a combination of high fat diet (HFD) feeding models and hyperlipidemic mouse models have been used to investigate the effects of dyslipidemia on skeletal homeostasis. In addition to the development of hypertriglyceridemia, these models exhibit a host of metabolic defects, including but not limited to adipose hyperplasia, hyperinsulinemia, insulin resistance, central leptin resistance, and hepatic steatosis [reviewed in ( 121 )], that can alter the balance of bone remodeling and influence bone strength. The consensus from the majority of these studies is that HFD feeding leads to a deterioration of trabecular bone mass at multiple skeletal sites in the axial and appendicular skeleton ( 60 , 116 , 122 – 126 ).…”

You Are What You Eat: Diet-Dependent Changes in Pulmonary Surfactant

“…These observations may have some important experimental implications in mouse models of pulmonary disease. Although most researchers feed their study subjects standardized chow, many cardiovascular and cancer studies employ modified (often high-fat) diets, and this may be an additional experimental variable that needs to be borne in mind when interpreting changes in lung function in these animals ( 8 , 9 ). More importantly, it is possible that surfactant function could be altered by changes in food intake associated with either incorporation of unpalatable chemicals in the chow or the onset of experimentally induced disease.…”